X-129792351-C-T

Variant names:

• chrX-129792351-C-T
• rs747669832
• NM_018990.4:c.466C>T

Variant summary

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

The NM_018990.4(SASH3):​c.466C>T​(p.Pro156Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000994 in 1,207,554 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 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 0.000027 (0 hom., 1 hem., cov: 23)
  • Exomes 𝑓: 0.0000082 (0 hom. 3 hem.)
• Consequence: SASH3 NM_018990.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.770
• 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=0.023525506).
• 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.466C>T	p.Pro156Ser	missense_variant	Exon 5 of 8	ENST00000356892.4	NP_061863.1
SASH3	XM_006724763.1	c.466C>T	p.Pro156Ser	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.466C>T	p.Pro156Ser	missense_variant	Exon 5 of 8	1	NM_018990.4	ENSP00000349359.3

Frequencies

GnomAD3 genomes AF: 0.0000268 AC: 3 AN: 112123 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: 0.00

Gnomad SAS AF: 0.000368

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00417

Gnomad NFE AF: 0.0000188

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000169 AC: 3 AN: 177230 AF XY: 0.0000160

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000254

Gnomad OTH exome AF: 0.000228

GnomAD4 exome AF: 0.00000822 AC: 9 AN: 1095379 Hom.: 0 Cov.: 31 AF XY: 0.00000830 AC XY: 3 AN XY: 361245

African (AFR) AF: 0.00 AC: 0 AN: 26379

American (AMR) AF: 0.0000286 AC: 1 AN: 35000

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19072

East Asian (EAS) AF: 0.00 AC: 0 AN: 30199

South Asian (SAS) AF: 0.00 AC: 0 AN: 53595

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40409

Middle Eastern (MID) AF: 0.000243 AC: 1 AN: 4112

European-Non Finnish (NFE) AF: 0.00000595 AC: 5 AN: 840629

Other (OTH) AF: 0.0000435 AC: 2 AN: 45984

GnomAD4 genome AF: 0.0000267 AC: 3 AN: 112175 Hom.: 0 Cov.: 23 AF XY: 0.0000291 AC XY: 1 AN XY: 34343

African (AFR) AF: 0.00 AC: 0 AN: 30925

American (AMR) AF: 0.00 AC: 0 AN: 10614

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2658

East Asian (EAS) AF: 0.00 AC: 0 AN: 3571

South Asian (SAS) AF: 0.000369 AC: 1 AN: 2710

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6131

Middle Eastern (MID) AF: 0.00457 AC: 1 AN: 219

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53139

Other (OTH) AF: 0.00 AC: 0 AN: 1527

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 28, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.466C>T (p.P156S) alteration is located in exon 5 (coding exon 5) of the SASH3 gene. This alteration results from a C to T substitution at nucleotide position 466, causing the proline (P) at amino acid position 156 to be replaced by a serine (S). 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	0.065
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.95
CADD	Benign	10
DANN	Benign	0.69
DEOGEN2	Benign	0.10	T
FATHMM_MKL	Benign	0.47	N
LIST_S2	Benign	0.60	T
M_CAP	Benign	0.0083	T
MetaRNN	Benign	0.024	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.60	N
PhyloP100		0.77
PrimateAI	Benign	0.39	T
PROVEAN	Benign	1.2	N
REVEL	Benign	0.022
Sift	Benign	1.0	T
Sift4G	Benign	0.67	T
Polyphen		0.0	B
Vest4		0.047
MutPred		0.29		Gain of phosphorylation at P156 (P = 0.0055);
MVP		0.11
MPC		0.48
ClinPred		0.052	T
GERP RS		3.0
Varity_R		0.047
gMVP		0.32
Mutation Taster		=91/9	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

dbSNP: rs747669832; hg19: chrX-128926327; COSMIC: COSV63556115; COSMIC: COSV63556115;