X-129792765-C-T

Variant names:

• chrX-129792765-C-T
• rs147976313
• NM_018990.4:c.730C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_018990.4(SASH3):​c.730C>T​(p.Arg244Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000562 in 1,205,822 control chromosomes in the GnomAD database, including 1 homozygotes. There are 209 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R244H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00038 (0 hom., 8 hem., cov: 23)
  • Exomes 𝑓: 0.00058 (1 hom. 201 hem.)
• Consequence: SASH3 NM_018990.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.46
• Publications: 2 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0510979).
• BP6: Variant X-129792765-C-T is Benign according to our data. Variant chrX-129792765-C-T is described in ClinVar as [Benign]. Clinvar id is 731424.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Hemizygotes in GnomAd4 at 8 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SASH3	NM_018990.4	c.730C>T	p.Arg244Cys	missense_variant	Exon 6 of 8	ENST00000356892.4	NP_061863.1
SASH3	XM_006724763.1	c.880C>T	p.Arg294Cys	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.730C>T	p.Arg244Cys	missense_variant	Exon 6 of 8	1	NM_018990.4	ENSP00000349359.3

Frequencies

GnomAD3 genomes AF: 0.000377 AC: 42 AN: 111552 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000975

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000191

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000284

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000678

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000360 AC: 64 AN: 177715 AF XY: 0.000317

Gnomad AFR exome AF: 0.0000763

Gnomad AMR exome AF: 0.0000737

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000217

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000662

Gnomad OTH exome AF: 0.000453

GnomAD4 exome AF: 0.000581 AC: 636 AN: 1094217 Hom.: 1 Cov.: 32 AF XY: 0.000558 AC XY: 201 AN XY: 360471

African (AFR) AF: 0.0000758 AC: 2 AN: 26369

American (AMR) AF: 0.000114 AC: 4 AN: 35057

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19200

East Asian (EAS) AF: 0.0000331 AC: 1 AN: 30205

South Asian (SAS) AF: 0.0000931 AC: 5 AN: 53683

European-Finnish (FIN) AF: 0.0000260 AC: 1 AN: 38402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4123

European-Non Finnish (NFE) AF: 0.000710 AC: 597 AN: 841197

Other (OTH) AF: 0.000565 AC: 26 AN: 45981

GnomAD4 genome AF: 0.000376 AC: 42 AN: 111605 Hom.: 0 Cov.: 23 AF XY: 0.000237 AC XY: 8 AN XY: 33791

African (AFR) AF: 0.0000973 AC: 3 AN: 30822

American (AMR) AF: 0.000191 AC: 2 AN: 10488

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2648

East Asian (EAS) AF: 0.000285 AC: 1 AN: 3513

South Asian (SAS) AF: 0.00 AC: 0 AN: 2672

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5960

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.000678 AC: 36 AN: 53071

Other (OTH) AF: 0.00 AC: 0 AN: 1530

Alfa AF: 0.000512 Hom.: 18

Bravo AF: 0.000374

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.000346 AC: 1

ESP6500AA AF: 0.000261 AC: 1

ESP6500EA AF: 0.000595 AC: 4

ExAC AF: 0.000321 AC: 39

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jul 31, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.52
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.76	D
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.051	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L
PhyloP100		2.5
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-3.8	D
REVEL	Benign	0.098
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.014	D
Polyphen		0.0020	B
Vest4		0.054
MVP		0.20
MPC		0.67
ClinPred		0.070	T
GERP RS		4.4
Varity_R		0.35
gMVP		0.81
Mutation Taster		=75/25	polymorphism

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: rs147976313; hg19: chrX-128926741; COSMIC: COSV99071681; COSMIC: COSV99071681;