chrX-19537725-G-A

Variant names:

• chrX-19537725-G-A
• rs748353385
• NM_031892.3:c.1948C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_031892.3(SH3KBP1):​c.1948C>T​(p.Arg650Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000155 in 1,097,447 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 8 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R650L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.000015 (0 hom. 8 hem.)
• Consequence: SH3KBP1 NM_031892.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.66
• Publications: 4 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: LIMITED Submitted by: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS2: High Hemizygotes in GnomAdExome4 at 8 XL,Unknown gene

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.1948C>T	p.Arg650Trp	missense	Exon 17 of 18	NP_114098.1	Q5JPT6
	SH3KBP1	NM_001410756.1		c.2080C>T	p.Arg694Trp	missense	Exon 19 of 20	NP_001397685.1	Q5JPT2
	SH3KBP1	NM_001353891.2		c.2023C>T	p.Arg675Trp	missense	Exon 18 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.1948C>T	p.Arg650Trp	missense	Exon 17 of 18	ENSP00000380921.3	Q96B97-1
	SH3KBP1	ENST00000379698.8	TSL:1	c.1837C>T	p.Arg613Trp	missense	Exon 16 of 17	ENSP00000369020.4	Q96B97-2
	SH3KBP1	ENST00000379726.8	TSL:5	c.2080C>T	p.Arg694Trp	missense	Exon 19 of 20	ENSP00000369049.4	Q5JPT2

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 0.0000155 AC: 17 AN: 1097447 Hom.: 0 Cov.: 29 AF XY: 0.0000221 AC XY: 8 AN XY: 362805

African (AFR) AF: 0.00 AC: 0 AN: 26381

American (AMR) AF: 0.00 AC: 0 AN: 35200

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19373

East Asian (EAS) AF: 0.0000331 AC: 1 AN: 30198

South Asian (SAS) AF: 0.00 AC: 0 AN: 54120

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40528

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4135

European-Non Finnish (NFE) AF: 0.0000190 AC: 16 AN: 841440

Other (OTH) AF: 0.00 AC: 0 AN: 46072

GnomAD4 genome Cov.: 22

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Uncertain	0.073	D
BayesDel_noAF	Benign	-0.13
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.51	D
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.68	D
MetaRNN	Uncertain	0.43	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		2.7
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.24
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.023	D
Polyphen		1.0	D
Vest4		0.60
MutPred		0.34		Loss of disorder (P = 0.0778)
MVP		0.86
MPC		1.4
ClinPred		1.0	D
GERP RS		4.1
Varity_R		0.61
gMVP		0.22
Mutation Taster		=78/22	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs748353385; hg19: chrX-19555843; COSMIC: COSV65646415;