chr12-105144435-A-G

Variant names:

• chr12-105144435-A-G
• rs113419458
• NM_015275.3:c.2159A>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_015275.3(WASHC4):​c.2159A>G​(p.Asn720Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00024 in 1,612,546 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00023 (0 hom.)
• Consequence: WASHC4 NM_015275.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4 B:1
• Conservation: PhyloP100: 6.17
• Publications: 3 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.015016794).
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000305 (46/151036) while in subpopulation EAS AF = 0.00155 (8/5160). AF 95% confidence interval is 0.000771. There are 0 homozygotes in GnomAd4. There are 22 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WASHC4	NM_015275.3	MANE Select	c.2159A>G	p.Asn720Ser	missense	Exon 21 of 33	NP_056090.1	Q2M389-1
	WASHC4	NM_001293640.2		c.2162A>G	p.Asn721Ser	missense	Exon 21 of 33	NP_001280569.1	A0A087X256

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WASHC4	ENST00000332180.10	TSL:1 MANE Select	c.2159A>G	p.Asn720Ser	missense	Exon 21 of 33	ENSP00000328062.6	Q2M389-1
	WASHC4	ENST00000620430.5	TSL:1	c.2162A>G	p.Asn721Ser	missense	Exon 21 of 33	ENSP00000484713.1	A0A087X256
	WASHC4	ENST00000934676.1		c.2159A>G	p.Asn720Ser	missense	Exon 21 of 33	ENSP00000604735.1

Frequencies

GnomAD3 genomes AF: 0.000285 AC: 43 AN: 150946 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000656

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000132

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00155

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000740

Gnomad OTH AF: 0.000480

GnomAD2 exomes AF: 0.000325 AC: 81 AN: 249314 AF XY: 0.000333

Gnomad AFR exome AF: 0.000775

Gnomad AMR exome AF: 0.000232

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00195

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.000186

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000233 AC: 341 AN: 1461510 Hom.: 0 Cov.: 31 AF XY: 0.000232 AC XY: 169 AN XY: 727072

African (AFR) AF: 0.00120 AC: 40 AN: 33464

American (AMR) AF: 0.000224 AC: 10 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00366 AC: 145 AN: 39654

South Asian (SAS) AF: 0.000104 AC: 9 AN: 86240

European-Finnish (FIN) AF: 0.0000374 AC: 2 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.000103 AC: 114 AN: 1111754

Other (OTH) AF: 0.000348 AC: 21 AN: 60376

GnomAD4 genome AF: 0.000305 AC: 46 AN: 151036 Hom.: 0 Cov.: 31 AF XY: 0.000298 AC XY: 22 AN XY: 73792

African (AFR) AF: 0.000727 AC: 30 AN: 41270

American (AMR) AF: 0.000132 AC: 2 AN: 15172

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3458

East Asian (EAS) AF: 0.00155 AC: 8 AN: 5160

South Asian (SAS) AF: 0.00 AC: 0 AN: 4794

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10276

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.0000740 AC: 5 AN: 67602

Other (OTH) AF: 0.000476 AC: 1 AN: 2102

Alfa AF: 0.000710 Hom.: 0

Bravo AF: 0.000272

ExAC AF: 0.000364 AC: 44

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000296

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	3	-	not specified (3)
-	1	-	not provided (1)
-	-	1	WASHC4-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0076	T
Eigen	Benign	-0.14
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.015	T
MetaSVM	Benign	-1.1	T
PhyloP100		6.2
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.037
Sift	Benign	0.32	T
Sift4G	Benign	0.47	T
Polyphen		0.0010	B
Vest4		0.26
MVP		0.31
MPC		0.14
ClinPred		0.040	T
GERP RS		6.0
Varity_R		0.080
gMVP		0.37
Mutation Taster		=76/24	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs113419458; hg19: chr12-105538213;