X-129792738-G-A

Variant names:

• chrX-129792738-G-A
• NM_018990.4:c.703G>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_018990.4(SASH3):​c.703G>A​(p.Glu235Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: SASH3 NM_018990.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 10.0

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SASH3	NM_018990.4	c.703G>A	p.Glu235Lys	missense_variant	Exon 6 of 8	ENST00000356892.4	NP_061863.1
SASH3	XM_006724763.1	c.853G>A	p.Glu285Lys	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	c.703G>A	p.Glu235Lys	missense_variant	Exon 6 of 8	1	NM_018990.4	ENSP00000349359.3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 26, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.703G>A (p.E235K) alteration is located in exon 6 (coding exon 6) of the SASH3 gene. This alteration results from a G to A substitution at nucleotide position 703, causing the glutamic acid (E) at amino acid position 235 to be replaced by a lysine (K). 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	0.19
BayesDel_addAF	Uncertain	0.078	D
BayesDel_noAF	Benign	-0.13
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.78	D
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.058	D
MetaRNN	Uncertain	0.74	D
MetaSVM	Benign	-0.68	T
MutationAssessor	Uncertain	2.0	M
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.34
Sift	Benign	0.11	T
Sift4G	Benign	0.12	T
Polyphen		1.0	D
Vest4		0.60
MutPred		0.56		Gain of ubiquitination at E235 (P = 0.0104);
MVP		0.61
MPC		1.4
ClinPred		0.98	D
GERP RS		5.3
Varity_R		0.65
gMVP		0.90

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-128926714;