rs74426960

Variant names:

• chr12-105144438-G-A
• rs74426960
• NM_015275.3:c.2162G>A

Your query was ambiguous. Multiple possible variants found:

• chr12-105144438-G-A
• chr12-105144438-G-C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_015275.3(WASHC4):​c.2162G>A​(p.Arg721His) variant causes a missense change. The variant allele was found at a frequency of 0.000504 in 1,610,564 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R721S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0024 (3 hom., cov: 31)
  • Exomes 𝑓: 0.00031 (2 hom.)
• Consequence: WASHC4 NM_015275.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 6.88
• Publications: 6 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009955913).
• BP6: Variant 12-105144438-G-A is Benign according to our data. Variant chr12-105144438-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 435577.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00242 (361/149286) while in subpopulation AFR AF = 0.00827 (337/40768). AF 95% confidence interval is 0.00754. There are 3 homozygotes in GnomAd4. There are 178 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR,Unknown gene

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.2162G>A	p.Arg721His	missense	Exon 21 of 33	NP_056090.1
	WASHC4	NM_001293640.2		c.2165G>A	p.Arg722His	missense	Exon 21 of 33	NP_001280569.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WASHC4	ENST00000332180.10	TSL:1 MANE Select	c.2162G>A	p.Arg721His	missense	Exon 21 of 33	ENSP00000328062.6
	WASHC4	ENST00000620430.5	TSL:1	c.2165G>A	p.Arg722His	missense	Exon 21 of 33	ENSP00000484713.1
	WASHC4	ENST00000311317.8	TSL:2	n.2249G>A		non_coding_transcript_exon	Exon 21 of 25

Frequencies

GnomAD3 genomes AF: 0.00242 AC: 361 AN: 149244 Hom.: 3 Cov.: 31

Gnomad AFR AF: 0.00828

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00106

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000743

Gnomad OTH AF: 0.00146

GnomAD2 exomes AF: 0.000594 AC: 148 AN: 249244 AF XY: 0.000466

Gnomad AFR exome AF: 0.00840

Gnomad AMR exome AF: 0.000319

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000556

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000442

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000309 AC: 451 AN: 1461278 Hom.: 2 Cov.: 31 AF XY: 0.000260 AC XY: 189 AN XY: 726950

African (AFR) AF: 0.00876 AC: 293 AN: 33434

American (AMR) AF: 0.000335 AC: 15 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26118

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39648

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000981 AC: 109 AN: 1111576

Other (OTH) AF: 0.000497 AC: 30 AN: 60374

GnomAD4 genome AF: 0.00242 AC: 361 AN: 149286 Hom.: 3 Cov.: 31 AF XY: 0.00245 AC XY: 178 AN XY: 72698

African (AFR) AF: 0.00827 AC: 337 AN: 40768

American (AMR) AF: 0.00106 AC: 16 AN: 15046

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3452

East Asian (EAS) AF: 0.00 AC: 0 AN: 5116

South Asian (SAS) AF: 0.00 AC: 0 AN: 4738

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9632

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 284

European-Non Finnish (NFE) AF: 0.0000743 AC: 5 AN: 67266

Other (OTH) AF: 0.00145 AC: 3 AN: 2074

Alfa AF: 0.00112 Hom.: 2

Bravo AF: 0.00290

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00915 AC: 33

ESP6500EA AF: 0.000123 AC: 1

ExAC AF: 0.000596 AC: 72

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Jan 19, 2017

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.32
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0064	T
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-1.1	T
PhyloP100		6.9
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-0.33	N
REVEL	Benign	0.15
Sift	Benign	0.20	T
Sift4G	Benign	0.14	T
Polyphen		0.98	D
Vest4		0.42
MVP		0.78
MPC		0.55
ClinPred		0.079	T
GERP RS		6.0
Varity_R		0.13
gMVP		0.71
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs74426960; hg19: chr12-105538216; COSMIC: COSV99046039; COSMIC: COSV99046039;