12-105121104-A-T

Variant names:

• chr12-105121104-A-T
• rs755388226
• NM_015275.3:c.565A>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015275.3(WASHC4):​c.565A>T​(p.Met189Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000687 in 1,456,106 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. 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. M189V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: WASHC4 NM_015275.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.12
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22643697).

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.565A>T	p.Met189Leu	missense	Exon 9 of 33	NP_056090.1	Q2M389-1
	WASHC4	NM_001293640.2		c.565A>T	p.Met189Leu	missense	Exon 9 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.565A>T	p.Met189Leu	missense	Exon 9 of 33	ENSP00000328062.6	Q2M389-1
	WASHC4	ENST00000620430.5	TSL:1	c.565A>T	p.Met189Leu	missense	Exon 9 of 33	ENSP00000484713.1	A0A087X256
	WASHC4	ENST00000934676.1		c.565A>T	p.Met189Leu	missense	Exon 9 of 33	ENSP00000604735.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1456106 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 724778

African (AFR) AF: 0.00 AC: 0 AN: 33344

American (AMR) AF: 0.00 AC: 0 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26094

East Asian (EAS) AF: 0.00 AC: 0 AN: 39568

South Asian (SAS) AF: 0.00 AC: 0 AN: 86152

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53070

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 9.03e-7 AC: 1 AN: 1107194

Other (OTH) AF: 0.00 AC: 0 AN: 60220

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.073	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	23
DANN	Benign	0.96
DEOGEN2	Benign	0.0014	T
Eigen	Benign	-0.20
Eigen_PC	Benign	0.055
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.85	T
M_CAP	Benign	0.0063	T
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-1.1	T
PhyloP100		5.1
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	0.080	N
REVEL	Benign	0.15
Sift	Uncertain	0.027	D
Sift4G	Benign	0.37	T
Polyphen		0.0070	B
Vest4		0.37
MutPred		0.38		Gain of catalytic residue at V184 (P = 0.005)
MVP		0.20
MPC		0.17
ClinPred		0.77	D
GERP RS		5.5
Varity_R		0.28
gMVP		0.38
Mutation Taster		=82/18	polymorphism

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

Other links and lift over

dbSNP: rs755388226; hg19: chr12-105514882;