chr12-105152340-T-G

Variant names:

• chr12-105152340-T-G
• rs773697401
• NM_015275.3:c.2650-3T>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_015275.3(WASHC4):​c.2650-3T>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: WASHC4 NM_015275.3 splice_region, intron
• Scores: Splicing: ADA: 0.9911
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.811
• Publications: 0 publications found

Genes affected

WASHC4 (HGNC:29174): (WASH complex subunit 4) This gene encodes a component of the WASH complex, which functions in the intracellular transport of endosomes. Mutations in this gene have been detected in individuals with autosomal recessive cognitive disability. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jun 2014]

WASHC4 Gene-Disease associations (from GenCC):

• autosomal recessive non-syndromic intellectual disability

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• intellectual disability, autosomal recessive 43

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics
• schizophrenia

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015275.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WASHC4	NM_015275.3	MANE Select	c.2650-3T>G		splice_region intron	N/A	NP_056090.1
	WASHC4	NM_001293640.2		c.2653-3T>G		splice_region intron	N/A	NP_001280569.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WASHC4	ENST00000332180.10	TSL:1 MANE Select	c.2650-3T>G		splice_region intron	N/A	ENSP00000328062.6
	WASHC4	ENST00000620430.5	TSL:1	c.2653-3T>G		splice_region intron	N/A	ENSP00000484713.1
	WASHC4	ENST00000550053.5	TSL:5	n.*2092-3T>G		splice_region intron	N/A	ENSP00000448966.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 21

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 30, 2016

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	14
DANN	Benign	0.87
PhyloP100		0.81
PromoterAI		0.0012	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.74
SpliceAI score (max)		0.65		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.36		Position offset: 17
DS_AL_spliceai		0.65		Position offset: 3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs773697401; hg19: chr12-105546118;