X-129792744-G-A

Variant names:

• chrX-129792744-G-A
• rs200789186
• NM_018990.4:c.709G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_018990.4(SASH3):​c.709G>A​(p.Val237Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000414 in 1,208,204 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 17 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 1 hem., cov: 23)
  • Exomes 𝑓: 0.000045 (0 hom. 16 hem.)
• Consequence: SASH3 NM_018990.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.19
• Publications: 1 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.019533813).
• BS2: High Hemizygotes in GnomAdExome4 at 16 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SASH3	NM_018990.4	c.709G>A	p.Val237Met	missense_variant	Exon 6 of 8	ENST00000356892.4	NP_061863.1
SASH3	XM_006724763.1	c.859G>A	p.Val287Met	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.709G>A	p.Val237Met	missense_variant	Exon 6 of 8	1	NM_018990.4	ENSP00000349359.3

Frequencies

GnomAD3 genomes AF: 0.00000893 AC: 1 AN: 112039 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000283

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000105 AC: 19 AN: 180738 AF XY: 0.0000913

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000940

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000615

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000447 AC: 49 AN: 1096113 Hom.: 0 Cov.: 32 AF XY: 0.0000442 AC XY: 16 AN XY: 361907

African (AFR) AF: 0.00 AC: 0 AN: 26397

American (AMR) AF: 0.00 AC: 0 AN: 35174

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19348

East Asian (EAS) AF: 0.000761 AC: 23 AN: 30206

South Asian (SAS) AF: 0.0000555 AC: 3 AN: 54044

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39113

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4132

European-Non Finnish (NFE) AF: 0.0000202 AC: 17 AN: 841647

Other (OTH) AF: 0.000130 AC: 6 AN: 46052

GnomAD4 genome AF: 0.00000892 AC: 1 AN: 112091 Hom.: 0 Cov.: 23 AF XY: 0.0000292 AC XY: 1 AN XY: 34259

African (AFR) AF: 0.00 AC: 0 AN: 30953

American (AMR) AF: 0.00 AC: 0 AN: 10601

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2654

East Asian (EAS) AF: 0.000284 AC: 1 AN: 3518

South Asian (SAS) AF: 0.00 AC: 0 AN: 2699

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6060

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 217

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53164

Other (OTH) AF: 0.00 AC: 0 AN: 1541

Alfa AF: 0.000142 Hom.: 1

Bravo AF: 0.0000529

ExAC AF: 0.0000741 AC: 9

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 16, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.709G>A (p.V237M) 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 709, causing the valine (V) at amino acid position 237 to be replaced by a methionine (M). 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	0.083
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.91
CADD	Benign	8.4
DANN	Benign	0.93
DEOGEN2	Benign	0.24	T
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.020	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
PhyloP100		1.2
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.59	N
REVEL	Benign	0.014
Sift	Benign	0.074	T
Sift4G	Benign	0.12	T
Polyphen		0.0010	B
Vest4		0.036
MVP		0.25
MPC		0.46
ClinPred		0.010	T
GERP RS		0.86
Varity_R		0.052
gMVP		0.73
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs200789186; hg19: chrX-128926720;