Genetic Variant SASH3:p.Val40Met (chrX-129788035-G-A) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_018990.4(SASH3):c.118G>A(p.Val40Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000292 in 1,200,284 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 8 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000064 ( 0 hom., 1 hem., cov: 22)

Exomes 𝑓: 0.000026 ( 0 hom. 7 hem. )

Consequence

SASH3
NM_018990.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.86

Publications

1 publications found

Variant links:

Genes affected

SASH3 (HGNC:15975): (SAM and SH3 domain containing 3) The protein encoded by this gene contains a Src homology-3 (SH3) domain and a sterile alpha motif (SAM), both of which are found in proteins involved in cell signaling. This protein may function as a signaling adapter protein in lymphocytes.[provided by RefSeq, Sep 2009]

SASH3 Gene-Disease associations (from GenCC):

immunodeficiency 102
Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
combined immunodeficiency, X-linked
Inheritance: XL Classification: STRONG Submitted by: ClinGen

SASH3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BS2

High Hemizygotes in GnomAdExome4 at 7 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SASH3	NM_018990.4 link	c.118G>A	p.Val40Met	missense_variant	Exon 2 of 8	ENST00000356892.4	NP_061863.1	O75995
SASH3	XM_006724763.1 link	c.118G>A	p.Val40Met	missense_variant	Exon 2 of 7		XP_006724826.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SASH3	ENST00000356892.4 link	c.118G>A	p.Val40Met	missense_variant	Exon 2 of 8	1	NM_018990.4	ENSP00000349359.3		O75995
SASH3	ENST00000476532.1 link	n.237G>A		non_coding_transcript_exon_variant	Exon 2 of 2	2

Frequencies

GnomAD3 genomes

AF:

0.0000641

AC:

AN:

109166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000668

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000403

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000763

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000110

AC:

AN:

182034

AF XY:

0.0000150

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000246

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000257

AC:

AN:

1091076

Hom.:

Cov.:

AF XY:

0.0000196

AC XY:

AN XY:

357264

show subpopulations

African (AFR)

AF:

0.000114

AC:

AN:

26242

American (AMR)

AF:

0.0000286

AC:

AN:

35010

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19202

East Asian (EAS)

AF:

0.00

AC:

AN:

29819

South Asian (SAS)

AF:

0.0000185

AC:

AN:

53984

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39993

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4074

European-Non Finnish (NFE)

AF:

0.0000275

AC:

AN:

837038

Other (OTH)

AF:

0.00

AC:

AN:

45714

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000641

AC:

AN:

109208

Hom.:

Cov.:

AF XY:

0.0000317

AC XY:

AN XY:

31580

show subpopulations

African (AFR)

AF:

0.0000667

AC:

AN:

30002

American (AMR)

AF:

0.00

AC:

AN:

10223

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2629

East Asian (EAS)

AF:

0.00

AC:

AN:

3415

South Asian (SAS)

AF:

0.000404

AC:

AN:

2476

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5658

Middle Eastern (MID)

AF:

0.00

AC:

AN:

215

European-Non Finnish (NFE)

AF:

0.0000763

AC:

AN:

52450

Other (OTH)

AF:

0.00

AC:

AN:

1465

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000340

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.000110

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 02, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.118G>A (p.V40M) alteration is located in exon 2 (coding exon 2) of the SASH3 gene. This alteration results from a G to A substitution at nucleotide position 118, causing the valine (V) at amino acid position 40 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.40

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.27

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.92

M_CAP

Pathogenic

0.37

MetaRNN

Benign

0.40

MetaSVM

Benign

-0.85

MutationAssessor

Uncertain

2.2

PhyloP100

4.9

PrimateAI

Uncertain

0.76

PROVEAN

Benign

-0.65

REVEL

Benign

0.14

Sift

Benign

0.11

Sift4G

Benign

0.18

Polyphen

1.0

Vest4

0.31

MutPred

0.12

Loss of loop (P = 0.0603);

MVP

0.62

MPC

1.3

ClinPred

0.69

GERP RS

5.2

Varity_R

0.20

gMVP

0.35

Mutation Taster

=85/15

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.24

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.24

Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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X-129788035-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over