Genetic Variant NM_018990.4:c.712G>C (chrX-129792747-G-C) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_018990.4(SASH3):c.712G>C(p.Gly238Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000109 in 1,096,208 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 0.000011 ( 0 hom. 4 hem. )

Consequence

SASH3
NM_018990.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.30

Publications

0 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 -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.10948527).

BS2

High Hemizygotes in GnomAdExome4 at 4 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SASH3	NM_018990.4 link	c.712G>C	p.Gly238Arg	missense_variant	Exon 6 of 8	ENST00000356892.4	NP_061863.1	O75995
SASH3	XM_006724763.1 link	c.862G>C	p.Gly288Arg	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.712G>C	p.Gly238Arg	missense_variant	Exon 6 of 8	1	NM_018990.4	ENSP00000349359.3		O75995

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.0000109

AC:

AN:

1096208

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

362006

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26395

American (AMR)

AF:

0.00

AC:

AN:

35157

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19334

East Asian (EAS)

AF:

0.00

AC:

AN:

30205

South Asian (SAS)

AF:

0.00

AC:

AN:

54034

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39054

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4134

European-Non Finnish (NFE)

AF:

0.0000143

AC:

AN:

841846

Other (OTH)

AF:

0.00

AC:

AN:

46049

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.531

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 26, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.712G>C (p.G238R) alteration is located in exon 6 (coding exon 6) of the SASH3 gene. This alteration results from a G to C substitution at nucleotide position 712, causing the glycine (G) at amino acid position 238 to be replaced by an arginine (R). 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

0.15

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.71

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.16

FATHMM_MKL

Benign

0.35

LIST_S2

Benign

0.78

M_CAP

Benign

0.013

MetaRNN

Benign

0.11

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

PhyloP100

2.3

PrimateAI

Uncertain

0.54

PROVEAN

Benign

0.96

REVEL

Benign

0.026

Sift

Benign

0.38

Sift4G

Benign

0.37

Polyphen

0.58

Vest4

0.20

MutPred

0.25

Gain of MoRF binding (P = 0.0276);

MVP

0.29

MPC

0.62

ClinPred

0.23

GERP RS

3.5

Varity_R

0.072

gMVP

0.83

Mutation Taster

=89/11

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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NM_018990.4:c.712G>C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over