X-129790968-C-G

Variant names:

• chrX-129790968-C-G
• NM_018990.4:c.329C>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_018990.4(SASH3):​c.329C>G​(p.Ser110Cys) 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. 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: 22)
• Consequence: SASH3 NM_018990.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.88
• Publications: 0 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM1: In a modified_residue Phosphoserine (size 0) in uniprot entity SASH3_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31722546).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SASH3	NM_018990.4	c.329C>G	p.Ser110Cys	missense_variant	Exon 4 of 8	ENST00000356892.4	NP_061863.1
SASH3	XM_006724763.1	c.329C>G	p.Ser110Cys	missense_variant	Exon 4 of 7		XP_006724826.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SASH3	ENST00000356892.4	c.329C>G	p.Ser110Cys	missense_variant	Exon 4 of 8	1	NM_018990.4	ENSP00000349359.3

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Immunodeficiency 102 Uncertain:1

-

Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Pirogov Russian National Research Medical University

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SASH3(NM_018990.4):c.329C>G (p.Ser110Cys) This is a missense variant that results in an amino acid substitution. This variant has not been observed in control samples or in patients with Immunodeficiency 102 (OMIM: 301082), fulfilling the PM2 criterion. Additionally, the description of the proband is very similar to clinical cases described, hence the PP4 criterion applies. Based on the applied ACMG/AMP criteria (PM2, PP4), this variant is classified as a Variant of Uncertain Significance (VUS) Immunodeficiency 102 (OMIM: 301082) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	T
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.32	T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	1.3	L
PhyloP100		2.9
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.10
Sift	Benign	0.070	T
Sift4G	Uncertain	0.029	D
Polyphen		0.99	D
Vest4		0.44
MutPred		0.24		Loss of phosphorylation at S110 (P = 0.0062);
MVP		0.31
MPC		0.46
ClinPred		0.83	D
GERP RS		5.7
Varity_R		0.25
gMVP		0.45
Mutation Taster		=56/44	polymorphism

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

Other links and lift over

hg19: chrX-128924944;