chr12-105111175-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_015275.3(WASHC4):c.112T>C(p.Tyr38His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0198 in 1,605,798 control chromosomes in the GnomAD database, including 386 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.015 ( 18 hom., cov: 33)

Exomes 𝑓: 0.020 ( 368 hom. )

Consequence

WASHC4
NM_015275.3 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 7.86

Publications

12 publications found

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 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)

WASHC4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0053884387).

BP6

Variant 12-105111175-T-C is Benign according to our data. Variant chr12-105111175-T-C is described in ClinVar as Benign. ClinVar VariationId is 3055677.Status of the report is no_assertion_criteria_provided, 0 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0154 (2342/152284) while in subpopulation NFE AF = 0.0231 (1569/67992). AF 95% confidence interval is 0.0221. There are 18 homozygotes in GnomAd4. There are 1124 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 18 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WASHC4	NM_015275.3	MANE Select	c.112T>C	p.Tyr38His	missense	Exon 2 of 33	NP_056090.1	Q2M389-1
	WASHC4	NM_001293640.2		c.112T>C	p.Tyr38His	missense	Exon 2 of 33	NP_001280569.1	A0A087X256

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
WASHC4	ENST00000332180.10	TSL:1 MANE Select	c.112T>C	p.Tyr38His	missense	Exon 2 of 33	ENSP00000328062.6	Q2M389-1
WASHC4	ENST00000620430.5	TSL:1	c.112T>C	p.Tyr38His	missense	Exon 2 of 33	ENSP00000484713.1	A0A087X256
WASHC4	ENST00000934676.1		c.112T>C	p.Tyr38His	missense	Exon 2 of 33	ENSP00000604735.1

Frequencies

GnomAD3 genomes

AF:

0.0154

AC:

2342

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00408

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0133

Gnomad ASJ

AF:

0.00720

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00496

Gnomad FIN

AF:

0.0306

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0231

Gnomad OTH

AF:

0.0115

GnomAD2 exomes

AF:

0.0149

AC:

3701

AN:

248980

AF XY:

0.0149

show subpopulations

Gnomad AFR exome

AF:

0.00304

Gnomad AMR exome

AF:

0.00889

Gnomad ASJ exome

AF:

0.00725

Gnomad EAS exome

AF:

0.0000557

Gnomad FIN exome

AF:

0.0293

Gnomad NFE exome

AF:

0.0204

Gnomad OTH exome

AF:

0.0157

GnomAD4 exome

AF:

0.0202

AC:

29388

AN:

1453514

Hom.:

368

Cov.:

AF XY:

0.0197

AC XY:

14289

AN XY:

723626

show subpopulations

African (AFR)

AF:

0.00288

AC:

AN:

33330

American (AMR)

AF:

0.00953

AC:

426

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.00736

AC:

192

AN:

26074

East Asian (EAS)

AF:

0.000126

AC:

AN:

39570

South Asian (SAS)

AF:

0.00856

AC:

737

AN:

86108

European-Finnish (FIN)

AF:

0.0283

AC:

1499

AN:

52986

Middle Eastern (MID)

AF:

0.0177

AC:

102

AN:

5748

European-Non Finnish (NFE)

AF:

0.0228

AC:

25171

AN:

1104900

Other (OTH)

AF:

0.0193

AC:

1160

AN:

60088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

1362

2723

4085

5446

6808

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

936

1872

2808

3744

4680

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0154

AC:

2342

AN:

152284

Hom.:

Cov.:

AF XY:

0.0151

AC XY:

1124

AN XY:

74448

show subpopulations

African (AFR)

AF:

0.00407

AC:

169

AN:

41568

American (AMR)

AF:

0.0133

AC:

203

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00720

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00497

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0306

AC:

325

AN:

10604

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0231

AC:

1569

AN:

67992

Other (OTH)

AF:

0.0114

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

118

236

354

472

590

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

140

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0202

Hom.:

Bravo

AF:

0.0134

TwinsUK

AF:

0.0189

AC:

ALSPAC

AF:

0.0223

AC:

ESP6500AA

AF:

0.00414

AC:

ESP6500EA

AF:

0.0191

AC:

155

ExAC

AF:

0.0148

AC:

1788

Asia WGS

AF:

0.00404

AC:

AN:

3476

EpiCase

AF:

0.0211

EpiControl

AF:

0.0181

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

WASHC4-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.65

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.36

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.0051

Eigen

Benign

0.10

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.93

MetaRNN

Benign

0.0054

MetaSVM

Benign

-1.1

PhyloP100

7.9

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

-1.1

REVEL

Benign

0.14

Sift

Benign

0.38

Sift4G

Benign

0.43

Polyphen

0.30

Vest4

0.48

MPC

0.41

ClinPred

0.047

GERP RS

5.6

Varity_R

0.32

gMVP

0.67

Mutation Taster

=82/18

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over