X-129792747-G-C

Variant names:

• chrX-129792747-G-C
• NM_018990.4:c.712G>C

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_018990.4(SASH3):​c.712G>C​(p.Gly238Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000109 in 1,096,208 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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.000011 (0 hom. 4 hem.)
• Consequence: SASH3 NM_018990.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.30
• 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):

• combined immunodeficiency, X-linked

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• immunodeficiency 102

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.10948527).
• BS2: High Hemizygotes in GnomAdExome4 at 4 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018990.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SASH3	NM_018990.4	MANE Select	c.712G>C	p.Gly238Arg	missense	Exon 6 of 8	NP_061863.1	O75995

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SASH3	ENST00000356892.4	TSL:1 MANE Select	c.712G>C	p.Gly238Arg	missense	Exon 6 of 8	ENSP00000349359.3	O75995

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.0000109 AC: 12 AN: 1096208 Hom.: 0 Cov.: 32 AF XY: 0.0000110 AC XY: 4 AN XY: 362006

African (AFR) AF: 0.00 AC: 0 AN: 26395

American (AMR) AF: 0.00 AC: 0 AN: 35157

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19334

East Asian (EAS) AF: 0.00 AC: 0 AN: 30205

South Asian (SAS) AF: 0.00 AC: 0 AN: 54034

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39054

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4134

European-Non Finnish (NFE) AF: 0.0000143 AC: 12 AN: 841846

Other (OTH) AF: 0.00 AC: 0 AN: 46049

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	16
DANN	Benign	0.97
DEOGEN2	Benign	0.16	T
FATHMM_MKL	Benign	0.35	N
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		2.3
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	0.96	N
REVEL	Benign	0.026
Sift	Benign	0.38	T
Sift4G	Benign	0.37	T
Polyphen		0.58	P
Vest4		0.20
MutPred		0.25		Gain of MoRF binding (P = 0.0276)
MVP		0.29
MPC		0.62
ClinPred		0.23	T
GERP RS		3.5
Varity_R		0.072
gMVP		0.83
Mutation Taster		=89/11	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

hg19: chrX-128926723;