12-105111242-A-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PM2 BP4_Strong BP6_Moderate BS1

The NM_015275.3(WASHC4):c.179A>G(p.Asn60Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000814 in 1,609,666 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000075 (0 hom.)
• Consequence: WASHC4 NM_015275.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.84

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 -8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0082834065).
• BP6: Variant 12-105111242-A-G is Benign according to our data. Variant chr12-105111242-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 747204.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000144 (22/152330) while in subpopulation EAS AF= 0.00328 (17/5188). AF 95% confidence interval is 0.00209. There are 0 homozygotes in gnomad4. There are 14 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WASHC4	NM_015275.3	c.179A>G	p.Asn60Ser	missense_variant	2/33	ENST00000332180.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WASHC4	ENST00000332180.10	c.179A>G	p.Asn60Ser	missense_variant	2/33	1	NM_015275.3	A1

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 152212 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00327

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000346 AC: 86 AN: 248636 Hom.: 0 AF XY: 0.000319 AC XY: 43 AN XY: 135000

Gnomad AFR exome AF: 0.0000648

Gnomad AMR exome AF: 0.0000580

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00395

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.0000474

Gnomad NFE exome AF: 0.0000266

Gnomad OTH exome AF: 0.000331

GnomAD4 exome AF: 0.0000748 AC: 109 AN: 1457336 Hom.: 0 Cov.: 28 AF XY: 0.0000827 AC XY: 60 AN XY: 725266

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00134

Gnomad4 SAS exome AF: 0.000221

Gnomad4 FIN exome AF: 0.0000190

Gnomad4 NFE exome AF: 0.0000253

Gnomad4 OTH exome AF: 0.0000830

GnomAD4 genome AF: 0.000144 AC: 22 AN: 152330 Hom.: 0 Cov.: 33 AF XY: 0.000188 AC XY: 14 AN XY: 74490

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00328

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000180 Hom.: 0

Bravo AF: 0.000140

ExAC AF: 0.000340 AC: 41

Asia WGS AF: 0.000289 AC: 1 AN: 3472

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.047
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.70
Cadd	Benign	18
Dann	Benign	0.85
DEOGEN2	Benign	0.0019	T;T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.066
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Benign	0.0022	T
MetaRNN	Benign	0.0083	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.72	N
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.36	N;.
REVEL	Benign	0.099
Sift	Benign	0.69	T;.
Sift4G	Benign	0.82	T;T
Polyphen		0.0	B;.
Vest4		0.20
MVP		0.21
MPC		0.14
ClinPred		0.014	T
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.037
gMVP		0.20

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: rs141620718; hg19: chr12-105505020;