dbSNP rs114844466: WASHC4:c.201+8T>G (chr12-105111272-T-G) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_015275.3(WASHC4):c.201+8T>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000862 in 1,582,702 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0045 ( 5 hom., cov: 33)

Exomes 𝑓: 0.00048 ( 5 hom. )

Consequence

WASHC4
NM_015275.3 splice_region, intron

Scores

Splicing: ADA: 0.0007076

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 2.72

Publications

0 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 -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.69).

BP6

Variant 12-105111272-T-G is Benign according to our data. Variant chr12-105111272-T-G is described in ClinVar as Benign. ClinVar VariationId is 790124.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00447 (681/152316) while in subpopulation AFR AF = 0.0156 (650/41586). AF 95% confidence interval is 0.0146. There are 5 homozygotes in GnomAd4. There are 323 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 5 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.201+8T>G		splice_region intron	N/A	NP_056090.1	Q2M389-1
	WASHC4	NM_001293640.2		c.201+8T>G		splice_region intron	N/A	NP_001280569.1	A0A087X256

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
WASHC4	ENST00000332180.10	TSL:1 MANE Select	c.201+8T>G	splice_region intron	N/A	ENSP00000328062.6	Q2M389-1
WASHC4	ENST00000620430.5	TSL:1	c.201+8T>G	splice_region intron	N/A	ENSP00000484713.1	A0A087X256
WASHC4	ENST00000934676.1		c.201+8T>G	splice_region intron	N/A	ENSP00000604735.1

Frequencies

GnomAD3 genomes

AF:

0.00446

AC:

679

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0156

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00111

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:

0.0000441

Gnomad OTH

AF:

0.00526

GnomAD2 exomes

AF:

0.00129

AC:

313

AN:

243414

AF XY:

0.000860

show subpopulations

Gnomad AFR exome

AF:

0.0171

Gnomad AMR exome

AF:

0.00129

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000904

Gnomad OTH exome

AF:

0.00118

GnomAD4 exome

AF:

0.000477

AC:

683

AN:

1430386

Hom.:

Cov.:

AF XY:

0.000393

AC XY:

280

AN XY:

712938

show subpopulations

African (AFR)

AF:

0.0160

AC:

526

AN:

32778

American (AMR)

AF:

0.00133

AC:

AN:

44426

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25862

East Asian (EAS)

AF:

0.00

AC:

AN:

39320

South Asian (SAS)

AF:

0.0000238

AC:

AN:

84184

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51498

Middle Eastern (MID)

AF:

0.00105

AC:

AN:

5698

European-Non Finnish (NFE)

AF:

0.0000166

AC:

AN:

1087378

Other (OTH)

AF:

0.00122

AC:

AN:

59242

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

119

149

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.00447

AC:

681

AN:

152316

Hom.:

Cov.:

AF XY:

0.00434

AC XY:

323

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.0156

AC:

650

AN:

41586

American (AMR)

AF:

0.00111

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68014

Other (OTH)

AF:

0.00520

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

108

144

180

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.000377

Hom.:

Bravo

AF:

0.00464

Asia WGS

AF:

0.000868

AC:

AN:

3470

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.69

CADD

Benign

7.6

(source)

DANN

Benign

0.77

PhyloP100

2.7

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00071

dbscSNV1_RF

Benign

0.0

SpliceAI score (max)

0.030

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