12-105144435-A-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_015275.3(WASHC4):​c.2159A>T​(p.Asn720Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,510 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N720S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: WASHC4 NM_015275.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.17
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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>T	p.Asn720Ile	missense	Exon 21 of 33	NP_056090.1	Q2M389-1
	WASHC4	NM_001293640.2		c.2162A>T	p.Asn721Ile	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>T	p.Asn720Ile	missense	Exon 21 of 33	ENSP00000328062.6	Q2M389-1
	WASHC4	ENST00000620430.5	TSL:1	c.2162A>T	p.Asn721Ile	missense	Exon 21 of 33	ENSP00000484713.1	A0A087X256
	WASHC4	ENST00000934676.1		c.2159A>T	p.Asn720Ile	missense	Exon 21 of 33	ENSP00000604735.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461510 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727072

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33464

American (AMR) AF: 0.00 AC: 0 AN: 44720

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39654

South Asian (SAS) AF: 0.00 AC: 0 AN: 86240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

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

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111754

Other (OTH) AF: 0.00 AC: 0 AN: 60376

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Benign	-0.058	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.072	T
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.027	D
MetaRNN	Uncertain	0.59	D
MetaSVM	Benign	-1.0	T
PhyloP100		6.2
PrimateAI	Uncertain	0.51	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Benign	0.10
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.033	D
Polyphen		0.17	B
Vest4		0.86
MutPred		0.42		Gain of catalytic residue at R717 (P = 0.0011)
MVP		0.63
MPC		0.22
ClinPred		0.99	D
GERP RS		6.0
Varity_R		0.59
gMVP		0.74
Mutation Taster		=71/29	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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;