12-105111175-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_015275.3(WASHC4):c.112T>C(p.Tyr38His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0198 in 1,605,798 control chromosomes in the GnomAD database, including 386 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.015 (18 hom., cov: 33)
  • Exomes 𝑓: 0.020 (368 hom.)
• Consequence: WASHC4 NM_015275.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 7.86

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0053884387).
• BP6: Variant 12-105111175-T-C is Benign according to our data. Variant chr12-105111175-T-C is described in ClinVar as [Benign]. Clinvar id is 3055677.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0154 (2342/152284) while in subpopulation NFE AF= 0.0231 (1569/67992). AF 95% confidence interval is 0.0221. There are 18 homozygotes in gnomad4. There are 1124 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 18 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WASHC4	NM_015275.3	c.112T>C	p.Tyr38His	missense_variant	2/33	ENST00000332180.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WASHC4	ENST00000332180.10	c.112T>C	p.Tyr38His	missense_variant	2/33	1	NM_015275.3	A1

Frequencies

GnomAD3 genomes AF: 0.0154 AC: 2342 AN: 152166 Hom.: 18 Cov.: 33

Gnomad AFR AF: 0.00408

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0133

Gnomad ASJ AF: 0.00720

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00496

Gnomad FIN AF: 0.0306

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0231

Gnomad OTH AF: 0.0115

GnomAD3 exomes AF: 0.0149 AC: 3701 AN: 248980 Hom.: 35 AF XY: 0.0149 AC XY: 2007 AN XY: 135146

Gnomad AFR exome AF: 0.00304

Gnomad AMR exome AF: 0.00889

Gnomad ASJ exome AF: 0.00725

Gnomad EAS exome AF: 0.0000557

Gnomad SAS exome AF: 0.00804

Gnomad FIN exome AF: 0.0293

Gnomad NFE exome AF: 0.0204

Gnomad OTH exome AF: 0.0157

GnomAD4 exome AF: 0.0202 AC: 29388 AN: 1453514 Hom.: 368 Cov.: 27 AF XY: 0.0197 AC XY: 14289 AN XY: 723626

Gnomad4 AFR exome AF: 0.00288

Gnomad4 AMR exome AF: 0.00953

Gnomad4 ASJ exome AF: 0.00736

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.00856

Gnomad4 FIN exome AF: 0.0283

Gnomad4 NFE exome AF: 0.0228

Gnomad4 OTH exome AF: 0.0193

GnomAD4 genome AF: 0.0154 AC: 2342 AN: 152284 Hom.: 18 Cov.: 33 AF XY: 0.0151 AC XY: 1124 AN XY: 74448

Gnomad4 AFR AF: 0.00407

Gnomad4 AMR AF: 0.0133

Gnomad4 ASJ AF: 0.00720

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00497

Gnomad4 FIN AF: 0.0306

Gnomad4 NFE AF: 0.0231

Gnomad4 OTH AF: 0.0114

Alfa AF: 0.0202 Hom.: 48

Bravo AF: 0.0134

TwinsUK AF: 0.0189 AC: 70

ALSPAC AF: 0.0223 AC: 86

ESP6500AA AF: 0.00414 AC: 15

ESP6500EA AF: 0.0191 AC: 155

ExAC AF: 0.0148 AC: 1788

Asia WGS AF: 0.00404 AC: 14 AN: 3476

EpiCase AF: 0.0211

EpiControl AF: 0.0181

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

WASHC4-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 05, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.36
Cadd	Benign	23
Dann	Uncertain	0.98
DEOGEN2	Benign	0.0051	T;T
Eigen	Benign	0.10
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D;D
MetaRNN	Benign	0.0054	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-1.1	N;.
REVEL	Benign	0.14
Sift	Benign	0.38	T;.
Sift4G	Benign	0.43	T;T
Polyphen		0.30	B;.
Vest4		0.48
MPC		0.41
ClinPred		0.047	T
GERP RS		5.6
Varity_R		0.32
gMVP		0.67

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs35294333; hg19: chr12-105504953; COSMIC: COSV99046035; COSMIC: COSV99046035;