X-129791067-G-T

Variant names:

• chrX-129791067-G-T
• rs758842379
• NM_018990.4:c.428G>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_018990.4(SASH3):​c.428G>T​(p.Arg143Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000456 in 1,096,815 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R143H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000046 (0 hom. 3 hem.)
• Consequence: SASH3 NM_018990.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.54
• 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: Likely_benign. The variant received -4 ACMG points.

• BS2: High Hemizygotes in GnomAdExome4 at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SASH3	NM_018990.4	c.428G>T	p.Arg143Leu	missense_variant	Exon 4 of 8	ENST00000356892.4	NP_061863.1
SASH3	XM_006724763.1	c.428G>T	p.Arg143Leu	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.428G>T	p.Arg143Leu	missense_variant	Exon 4 of 8	1	NM_018990.4	ENSP00000349359.3

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 0.00000456 AC: 5 AN: 1096815 Hom.: 0 Cov.: 30 AF XY: 0.00000828 AC XY: 3 AN XY: 362261

African (AFR) AF: 0.00 AC: 0 AN: 26357

American (AMR) AF: 0.00 AC: 0 AN: 35093

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19332

East Asian (EAS) AF: 0.00 AC: 0 AN: 30139

South Asian (SAS) AF: 0.00 AC: 0 AN: 53894

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40476

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4042

European-Non Finnish (NFE) AF: 0.00000475 AC: 4 AN: 841452

Other (OTH) AF: 0.0000217 AC: 1 AN: 46030

GnomAD4 genome Cov.: 22

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.070	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.51	D
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.052	D
MetaRNN	Uncertain	0.47	T
MetaSVM	Benign	-0.77	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		5.5
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-3.2	D
REVEL	Benign	0.17
Sift	Benign	0.058	T
Sift4G	Benign	0.13	T
Polyphen		0.68	P
Vest4		0.56
MutPred		0.19		Loss of phosphorylation at S146 (P = 0.0893);
MVP		0.39
MPC		1.1
ClinPred		0.98	D
GERP RS		4.9
Varity_R		0.41
gMVP		0.61
Mutation Taster		=49/51	disease causing

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

Other links and lift over

dbSNP: rs758842379; hg19: chrX-128925043;