Genetic Variant SASH3:p.Arg244Cys (chrX-129792765-C-T) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_018990.4(SASH3):c.730C>T(p.Arg244Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000562 in 1,205,822 control chromosomes in the GnomAD database, including 1 homozygotes. There are 209 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R244H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00038 ( 0 hom., 8 hem., cov: 23)

Exomes 𝑓: 0.00058 ( 1 hom. 201 hem. )

Consequence

SASH3
NM_018990.4 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 2.46

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0510979).

BP6

Variant X-129792765-C-T is Benign according to our data. Variant chrX-129792765-C-T is described in ClinVar as [Benign]. Clinvar id is 731424.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Hemizygotes in GnomAd4 at 8 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SASH3	NM_018990.4 link	c.730C>T	p.Arg244Cys	missense_variant	Exon 6 of 8	ENST00000356892.4	NP_061863.1	O75995
SASH3	XM_006724763.1 link	c.880C>T	p.Arg294Cys	missense_variant	Exon 5 of 7		XP_006724826.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SASH3	ENST00000356892.4 link	c.730C>T	p.Arg244Cys	missense_variant	Exon 6 of 8	1	NM_018990.4	ENSP00000349359.3		O75995

Frequencies

GnomAD3 genomes

AF:

0.000377

AC:

AN:

111552

Hom.:

Cov.:

AF XY:

0.000237

AC XY:

AN XY:

33728

show subpopulations

Gnomad AFR

AF:

0.0000975

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000191

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000284

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000678

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000360

AC:

AN:

177715

Hom.:

AF XY:

0.000317

AC XY:

AN XY:

63149

show subpopulations

Gnomad AFR exome

AF:

0.0000763

Gnomad AMR exome

AF:

0.0000737

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000217

Gnomad SAS exome

AF:

0.000164

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000662

Gnomad OTH exome

AF:

0.000453

GnomAD4 exome

AF:

0.000581

AC:

636

AN:

1094217

Hom.:

Cov.:

AF XY:

0.000558

AC XY:

201

AN XY:

360471

show subpopulations

Gnomad4 AFR exome

AF:

0.0000758

Gnomad4 AMR exome

AF:

0.000114

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000331

Gnomad4 SAS exome

AF:

0.0000931

Gnomad4 FIN exome

AF:

0.0000260

Gnomad4 NFE exome

AF:

0.000710

Gnomad4 OTH exome

AF:

0.000565

GnomAD4 genome

AF:

0.000376

AC:

AN:

111605

Hom.:

Cov.:

AF XY:

0.000237

AC XY:

AN XY:

33791

show subpopulations

Gnomad4 AFR

AF:

0.0000973

Gnomad4 AMR

AF:

0.000191

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000285

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000678

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000512

Hom.:

Bravo

AF:

0.000374

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.000346

AC:

ESP6500AA

AF:

0.000261

AC:

ESP6500EA

AF:

0.000595

AC:

ExAC

AF:

0.000321

AC:

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Jul 31, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.52

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.76

FATHMM_MKL

Uncertain

0.82

LIST_S2

Uncertain

0.90

M_CAP

Benign

0.025

MetaRNN

Benign

0.051

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.7

PrimateAI

Uncertain

0.58

PROVEAN

Uncertain

-3.8

REVEL

Benign

0.098

Sift

Uncertain

0.013

Sift4G

Uncertain

0.014

Polyphen

0.0020

Vest4

0.054

MVP

0.20

MPC

0.67

ClinPred

0.070

GERP RS

4.4

Varity_R

0.35

gMVP

0.81

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