Variant chr12-105143146-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_015275.3(WASHC4):c.1913G>A(p.Arg638His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000603 in 1,609,356 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000060 ( 0 hom. )

Consequence

WASHC4
NM_015275.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 10.0

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WASHC4	NM_015275.3 linkuse as main transcript	c.1913G>A	p.Arg638His	missense_variant	20/33	ENST00000332180.10	NP_056090.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WASHC4	ENST00000332180.10 linkuse as main transcript	c.1913G>A	p.Arg638His	missense_variant	20/33	1	NM_015275.3	ENSP00000328062	A1	Q2M389-1
WASHC4	ENST00000620430.5 linkuse as main transcript	c.1916G>A	p.Arg639His	missense_variant	20/33	1		ENSP00000484713	P5
WASHC4	ENST00000311317.8 linkuse as main transcript	n.2000G>A		non_coding_transcript_exon_variant	20/25	2
WASHC4	ENST00000550053.5 linkuse as main transcript	c.*1355G>A		3_prime_UTR_variant, NMD_transcript_variant	20/33	5		ENSP00000448966

Frequencies

GnomAD3 genomes

AF:

0.0000658

AC:

AN:

151884

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.0000737

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.0000604

AC:

AN:

248298

Hom.:

AF XY:

0.0000594

AC XY:

AN XY:

134736

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000204

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000111

Gnomad SAS exome

AF:

0.0000328

Gnomad FIN exome

AF:

0.0000465

Gnomad NFE exome

AF:

0.0000267

Gnomad OTH exome

AF:

0.000166

GnomAD4 exome

AF:

0.0000597

AC:

AN:

1457472

Hom.:

Cov.:

AF XY:

0.0000552

AC XY:

AN XY:

725254

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000179

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000632

Gnomad4 OTH exome

AF:

0.0000332

GnomAD4 genome

AF:

0.0000658

AC:

AN:

151884

Hom.:

Cov.:

AF XY:

0.0000539

AC XY:

AN XY:

74172

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000737

Gnomad4 OTH

AF:

0.000479

Alfa

AF:

0.0000868

Hom.:

Bravo

AF:

0.0000793

ExAC

AF:

0.0000331

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	May 24, 2024	The c.1913G>A (p.R638H) alteration is located in exon 20 (coding exon 20) of the KIAA1033 gene. This alteration results from a G to A substitution at nucleotide position 1913, causing the arginine (R) at amino acid position 638 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 07, 2017	- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2024

WASHC4: PM2:Supporting -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.22

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.0039

T;T

Eigen

Uncertain

0.68

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

D;D

M_CAP

Benign

0.010

MetaRNN

Uncertain

0.61

D;D

MetaSVM

Benign

-0.97

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-1.5

N;.

REVEL

Benign

0.23

Sift

Benign

0.039

D;.

Sift4G

Benign

0.16

T;T

Polyphen

0.98

D;.

Vest4

0.76

MVP

0.78

MPC

0.55

ClinPred

0.22

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.17

gMVP

0.59

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over