X-129792385-C-A

Variant names:

• chrX-129792385-C-A
• NM_018990.4:c.500C>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_018990.4(SASH3):​c.500C>A​(p.Ala167Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/20 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)
• Consequence: SASH3 NM_018990.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.69

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10052532).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SASH3	NM_018990.4	c.500C>A	p.Ala167Asp	missense_variant	Exon 5 of 8	ENST00000356892.4	NP_061863.1
SASH3	XM_006724763.1	c.500C>A	p.Ala167Asp	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.500C>A	p.Ala167Asp	missense_variant	Exon 5 of 8	1	NM_018990.4	ENSP00000349359.3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 19, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.500C>A (p.A167D) alteration is located in exon 5 (coding exon 5) of the SASH3 gene. This alteration results from a C to A substitution at nucleotide position 500, causing the alanine (A) at amino acid position 167 to be replaced by an aspartic acid (D). 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	-0.32	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.10	T
FATHMM_MKL	Benign	0.52	D
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.30	N
REVEL	Benign	0.076
Sift	Benign	0.54	T
Sift4G	Benign	0.62	T
Polyphen		0.28	B
Vest4		0.27
MutPred		0.20		Gain of relative solvent accessibility (P = 0.1066);
MVP		0.27
MPC		0.97
ClinPred		0.26	T
GERP RS		3.9
Varity_R		0.20
gMVP		0.62

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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-128926361;