chrX-19536452-C-T

Variant names:

• chrX-19536452-C-T
• rs1391119237
• NM_031892.3:c.1963G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_031892.3(SH3KBP1):​c.1963G>A​(p.Val655Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000178 in 112,132 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., 1 hem., cov: 22)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: SH3KBP1 NM_031892.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.75
• Publications: 0 publications found

Genes affected

SH3KBP1 (HGNC:13867): (SH3 domain containing kinase binding protein 1) This gene encodes an adapter protein that contains one or more N-terminal Src homology domains, a proline rich region and a C-terminal coiled-coil domain. The encoded protein facilitates protein-protein interactions and has been implicated in numerous cellular processes including apoptosis, cytoskeletal rearrangement, cell adhesion and in the regulation of clathrin-dependent endocytosis. Alternate splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Jul 2017]

SH3KBP1 Gene-Disease associations (from GenCC):

• immunodeficiency 61

  Inheritance: XL, Unknown Classification: MODERATE, LIMITED Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33869606).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_031892.3. 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
	SH3KBP1	NM_031892.3	MANE Select	c.1963G>A	p.Val655Met	missense	Exon 18 of 18	NP_114098.1	Q5JPT6
	SH3KBP1	NM_001410756.1		c.2095G>A	p.Val699Met	missense	Exon 20 of 20	NP_001397685.1	Q5JPT2
	SH3KBP1	NM_001353891.2		c.2038G>A	p.Val680Met	missense	Exon 19 of 19	NP_001340820.1	A0A8V8TP27

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SH3KBP1	ENST00000397821.8	TSL:1 MANE Select	c.1963G>A	p.Val655Met	missense	Exon 18 of 18	ENSP00000380921.3	Q96B97-1
	SH3KBP1	ENST00000379698.8	TSL:1	c.1852G>A	p.Val618Met	missense	Exon 17 of 17	ENSP00000369020.4	Q96B97-2
	SH3KBP1	ENST00000379726.8	TSL:5	c.2095G>A	p.Val699Met	missense	Exon 20 of 20	ENSP00000369049.4	Q5JPT2

Frequencies

GnomAD3 genomes AF: 0.0000178 AC: 2 AN: 112132 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.0000648

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1018041 Hom.: 0 Cov.: 19 AF XY: 0.00 AC XY: 0 AN XY: 302939

African (AFR) AF: 0.00 AC: 0 AN: 24594

American (AMR) AF: 0.00 AC: 0 AN: 32099

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18278

East Asian (EAS) AF: 0.00 AC: 0 AN: 28911

South Asian (SAS) AF: 0.00 AC: 0 AN: 47739

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40043

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3866

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 779386

Other (OTH) AF: 0.00 AC: 0 AN: 43125

GnomAD4 genome AF: 0.0000178 AC: 2 AN: 112132 Hom.: 0 Cov.: 22 AF XY: 0.0000292 AC XY: 1 AN XY: 34302

African (AFR) AF: 0.0000648 AC: 2 AN: 30858

American (AMR) AF: 0.00 AC: 0 AN: 10582

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2655

East Asian (EAS) AF: 0.00 AC: 0 AN: 3606

South Asian (SAS) AF: 0.00 AC: 0 AN: 2701

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6038

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53263

Other (OTH) AF: 0.00 AC: 0 AN: 1505

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Uncertain	0.046	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.34	T
MetaSVM	Benign	-0.74	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		5.8
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.12
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.63
MutPred		0.20		Gain of methylation at K660 (P = 0.1146)
MVP		0.76
MPC		1.4
ClinPred		0.95	D
GERP RS		5.1
Varity_R		0.78
gMVP		0.42
Mutation Taster		=67/33	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: rs1391119237; hg19: chrX-19554570;