chrX-129792369-G-A

Variant names:

• chrX-129792369-G-A
• rs776424343
• NM_018990.4:c.484G>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.484G>A​(p.Gly162Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000496 in 1,209,149 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 15 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 0.00012 (0 hom., 5 hem., cov: 23)
  • Exomes 𝑓: 0.000043 (0 hom. 10 hem.)
• Consequence: SASH3 NM_018990.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.660
• 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=0.009448141).
• BS2: High Hemizygotes in GnomAd4 at 5 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SASH3	NM_018990.4	c.484G>A	p.Gly162Arg	missense_variant	Exon 5 of 8	ENST00000356892.4	NP_061863.1
SASH3	XM_006724763.1	c.484G>A	p.Gly162Arg	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.484G>A	p.Gly162Arg	missense_variant	Exon 5 of 8	1	NM_018990.4	ENSP00000349359.3

Frequencies

GnomAD3 genomes AF: 0.000116 AC: 13 AN: 111950 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.000390

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000946

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

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: 0.0000886 AC: 16 AN: 180679 AF XY: 0.0000459

Gnomad AFR exome AF: 0.000837

Gnomad AMR exome AF: 0.000147

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000224

GnomAD4 exome AF: 0.0000428 AC: 47 AN: 1097149 Hom.: 0 Cov.: 31 AF XY: 0.0000276 AC XY: 10 AN XY: 362591

African (AFR) AF: 0.00102 AC: 27 AN: 26386

American (AMR) AF: 0.000114 AC: 4 AN: 35120

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19289

East Asian (EAS) AF: 0.0000662 AC: 2 AN: 30200

South Asian (SAS) AF: 0.0000185 AC: 1 AN: 53970

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40487

Middle Eastern (MID) AF: 0.000242 AC: 1 AN: 4125

European-Non Finnish (NFE) AF: 0.00000594 AC: 5 AN: 841517

Other (OTH) AF: 0.000152 AC: 7 AN: 46055

GnomAD4 genome AF: 0.000116 AC: 13 AN: 112000 Hom.: 0 Cov.: 23 AF XY: 0.000146 AC XY: 5 AN XY: 34192

African (AFR) AF: 0.000389 AC: 12 AN: 30872

American (AMR) AF: 0.0000945 AC: 1 AN: 10585

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2652

East Asian (EAS) AF: 0.00 AC: 0 AN: 3543

South Asian (SAS) AF: 0.00 AC: 0 AN: 2691

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6112

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 219

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53120

Other (OTH) AF: 0.00 AC: 0 AN: 1523

Alfa AF: 0.000217 Hom.: 1

Bravo AF: 0.000181

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

Mar 06, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.484G>A (p.G162R) alteration is located in exon 5 (coding exon 5) of the SASH3 gene. This alteration results from a G to A substitution at nucleotide position 484, causing the glycine (G) at amino acid position 162 to be replaced by an arginine (R). 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	0.071
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.91
CADD	Benign	11
DANN	Benign	0.93
DEOGEN2	Benign	0.19	T
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.66	T
M_CAP	Benign	0.0081	T
MetaRNN	Benign	0.0094	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-0.62	N
PhyloP100		0.66
PrimateAI	Benign	0.47	T
PROVEAN	Benign	3.1	N
REVEL	Benign	0.076
Sift	Benign	0.90	T
Sift4G	Benign	0.67	T
Polyphen		0.0030	B
Vest4		0.097
MutPred		0.24		Loss of glycosylation at S160 (P = 0.0746);
MVP		0.11
MPC		0.55
ClinPred		0.022	T
GERP RS		1.6
Varity_R		0.042
gMVP		0.40
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs776424343; hg19: chrX-128926345; COSMIC: COSV100795256; COSMIC: COSV100795256;