X-19536458-T-A

Variant names:

• chrX-19536458-T-A
• rs11248
• NM_031892.3:c.1957A>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_031892.3(SH3KBP1):​c.1957A>T​(p.Met653Leu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000099 in 1,010,239 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M653K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.9e-7 (0 hom. 0 hem.)
• Consequence: SH3KBP1 NM_031892.3 missense, splice_region
• Scores: Splicing: ADA: 0.003287
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.13
• 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: LIMITED Submitted by: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19445977).

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.1957A>T	p.Met653Leu	missense splice_region	Exon 18 of 18	NP_114098.1	Q5JPT6
	SH3KBP1	NM_001410756.1		c.2089A>T	p.Met697Leu	missense splice_region	Exon 20 of 20	NP_001397685.1	Q5JPT2
	SH3KBP1	NM_001353891.2		c.2032A>T	p.Met678Leu	missense splice_region	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.1957A>T	p.Met653Leu	missense splice_region	Exon 18 of 18	ENSP00000380921.3	Q96B97-1
	SH3KBP1	ENST00000379698.8	TSL:1	c.1846A>T	p.Met616Leu	missense splice_region	Exon 17 of 17	ENSP00000369020.4	Q96B97-2
	SH3KBP1	ENST00000379726.8	TSL:5	c.2089A>T	p.Met697Leu	missense splice_region	Exon 20 of 20	ENSP00000369049.4	Q5JPT2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.90e-7 AC: 1 AN: 1010239 Hom.: 0 Cov.: 18 AF XY: 0.00 AC XY: 0 AN XY: 297913

African (AFR) AF: 0.00 AC: 0 AN: 24414

American (AMR) AF: 0.00 AC: 0 AN: 31536

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18104

East Asian (EAS) AF: 0.00 AC: 0 AN: 28855

South Asian (SAS) AF: 0.00 AC: 0 AN: 47254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40017

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3852

European-Non Finnish (NFE) AF: 0.00000129 AC: 1 AN: 773335

Other (OTH) AF: 0.00 AC: 0 AN: 42872

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	21
DANN	Benign	0.87
DEOGEN2	Benign	0.14	T
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.0054	T
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L
PhyloP100		4.1
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-0.87	N
REVEL	Benign	0.20
Sift	Benign	0.29	T
Sift4G	Benign	0.39	T
Polyphen		0.0030	B
Vest4		0.36
MutPred		0.27		Loss of MoRF binding (P = 0.0716)
MVP		0.86
MPC		0.52
ClinPred		0.41	T
GERP RS		4.9
Varity_R		0.34
gMVP		0.090
Mutation Taster		=47/53	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0033
dbscSNV1_RF	Benign	0.096
SpliceAI score (max)		0.040		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: rs11248; hg19: chrX-19554576;