NM_016628.5(WAC):c.381+4_381+7del AND DeSanto-Shinawi syndrome due to WAC point mutation

Germline classification:: Conflicting interpretations of pathogenicity (4 submissions)
Last evaluated:: Mar 3, 2023
Review status:: criteria provided, conflicting classifications

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001253727.7

Allele description [Variation Report for NM_016628.5(WAC):c.381+4_381+7del]

NM_016628.5(WAC):c.381+4_381+7del

Gene:

WAC:WW domain containing adaptor with coiled-coil [Gene - OMIM - HGNC]

Variant type:

Microsatellite

Cytogenetic location:

10p12.1

Genomic location:

Preferred name:

NM_016628.5(WAC):c.381+4_381+7del

HGVS:

NC_000010.11:g.28583505AGTA[1]
NG_046603.1:g.55918AGTA[1]
NM_016628.5:c.381+4_381+7delMANE SELECT
NM_100264.3:c.246+4_246+7del
NM_100486.4:c.381+4_381+7del
NC_000010.10:g.28872434AGTA[1]
NM_016628.4:c.381+4_381+7del
NM_016628.4:c.381+4_381+7delAGTA

Links:

dbSNP: rs1564400647

NCBI 1000 Genomes Browser:

rs1564400647

Molecular consequence:

NM_016628.5:c.381+4_381+7del - splice donor variant - [Sequence Ontology: SO:0001575]
NM_100264.3:c.246+4_246+7del - splice donor variant - [Sequence Ontology: SO:0001575]
NM_100486.4:c.381+4_381+7del - splice donor variant - [Sequence Ontology: SO:0001575]

Observations:

Condition(s)

Name:: DeSanto-Shinawi syndrome due to WAC point mutation (DESSH)
Synonyms:: DEVELOPMENTAL DELAY, BEHAVIORAL ABNORMALITIES, FACIAL DYSMORPHISM, AND OCULAR ABNORMALITIES; Facial dysmorphism-developmental delay-behavioral abnormalities syndrome due to WAC point mutation
Identifiers:: MONDO: MONDO:0014741; MedGen: C5681129; Orphanet: 284169; OMIM: 616708

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001427241	Clinical Genomics Laboratory, Stanford Medicine	no assertion criteria provided	Uncertain significance (Jun 26, 2020)	germline	clinical testing
SCV001429580	Institute of Human Genetics, University of Leipzig Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jan 9, 2020)	de novo	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004032475	Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 3, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005324798	Laboratory of Medical Genetics Unit, Bambino Gesù Children's Hospital	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic	de novo	clinical testing	PubMed (1) [See all records that cite this PMID]

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	de novo	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Clinical Genomics Laboratory, Stanford Medicine, SCV001427241.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1		not provided	not provided	not provided	clinical testing	not provided

Description

The c.381+4_381+7delAGTA variant in the WAC gene was identified de novo in this individual, but has not been previously reported in association with disease.This variant was absent from large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/).The c.381+4_381+7delAGTA variant occurs in the 5â€™ splice site of intron 4 and computational tools predict that this variant causes a loss of the splice site.However, the accuracy of these computational tools is limited.These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, the significance of the c.381+4_381+7delAGTA variant is uncertain.However, there is suspicion that this variant could be associated with disease due to it being identified de novo in this individual and the predicted impact to splicing. Additional information is needed to resolve the significance of this variant. [ACMG evidence codes used: PS2_Supporting;PM2; PP3]

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Institute of Human Genetics, University of Leipzig Medical Center, SCV001429580.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (1)

Description

This variant was identified as de novo (maternity and paternity confirmed).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	de novo	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn, SCV004032475.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Laboratory of Medical Genetics Unit, Bambino Gesù Children's Hospital, SCV005324798.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1		not provided	not provided	not provided	clinical testing	PubMed (1)

Description

This variant was identified as de novo. The variant involves the intronic +5 splice site and splice predictors support a deleterious effect. It can be classified as likely pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	de novo	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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