chrX-19537724-C-T

Variant names:

• chrX-19537724-C-T
• rs142403021
• NM_031892.3:c.1949G>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_031892.3(SH3KBP1):​c.1949G>A​(p.Arg650Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00623 in 1,208,947 control chromosomes in the GnomAD database, including 26 homozygotes. There are 2,542 hemizygotes in GnomAD. In-silico tool predicts 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. R650L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0044 (0 hom., 145 hem., cov: 23)
  • Exomes 𝑓: 0.0064 (26 hom. 2397 hem.)
• Consequence: SH3KBP1 NM_031892.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.35
• Publications: 10 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: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0070169866).
• BP6: Variant X-19537724-C-T is Benign according to our data. Variant chrX-19537724-C-T is described in ClinVar as Benign. ClinVar VariationId is 1166220.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Hemizygotes in GnomAd4 at 145 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.1949G>A	p.Arg650Gln	missense	Exon 17 of 18	NP_114098.1	Q5JPT6
	SH3KBP1	NM_001410756.1		c.2081G>A	p.Arg694Gln	missense	Exon 19 of 20	NP_001397685.1	Q5JPT2
	SH3KBP1	NM_001353891.2		c.2024G>A	p.Arg675Gln	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.1949G>A	p.Arg650Gln	missense	Exon 17 of 18	ENSP00000380921.3	Q96B97-1
	SH3KBP1	ENST00000379698.8	TSL:1	c.1838G>A	p.Arg613Gln	missense	Exon 16 of 17	ENSP00000369020.4	Q96B97-2
	SH3KBP1	ENST00000379726.8	TSL:5	c.2081G>A	p.Arg694Gln	missense	Exon 19 of 20	ENSP00000369049.4	Q5JPT2

Frequencies

GnomAD3 genomes AF: 0.00442 AC: 493 AN: 111461 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.000947

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00114

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00559

Gnomad FIN AF: 0.00823

Gnomad MID AF: 0.0169

Gnomad NFE AF: 0.00703

Gnomad OTH AF: 0.00603

GnomAD2 exomes AF: 0.00443 AC: 812 AN: 183337 AF XY: 0.00506

Gnomad AFR exome AF: 0.000836

Gnomad AMR exome AF: 0.00193

Gnomad ASJ exome AF: 0.000801

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00681

Gnomad NFE exome AF: 0.00637

Gnomad OTH exome AF: 0.00618

GnomAD4 exome AF: 0.00642 AC: 7043 AN: 1097435 Hom.: 26 Cov.: 29 AF XY: 0.00661 AC XY: 2397 AN XY: 362829

African (AFR) AF: 0.000947 AC: 25 AN: 26386

American (AMR) AF: 0.00216 AC: 76 AN: 35201

Ashkenazi Jewish (ASJ) AF: 0.000929 AC: 18 AN: 19375

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

South Asian (SAS) AF: 0.00584 AC: 316 AN: 54116

European-Finnish (FIN) AF: 0.00664 AC: 269 AN: 40527

Middle Eastern (MID) AF: 0.0121 AC: 50 AN: 4134

European-Non Finnish (NFE) AF: 0.00714 AC: 6007 AN: 841419

Other (OTH) AF: 0.00610 AC: 281 AN: 46079

GnomAD4 genome AF: 0.00441 AC: 492 AN: 111512 Hom.: 0 Cov.: 23 AF XY: 0.00430 AC XY: 145 AN XY: 33712

African (AFR) AF: 0.000945 AC: 29 AN: 30701

American (AMR) AF: 0.00105 AC: 11 AN: 10526

Ashkenazi Jewish (ASJ) AF: 0.00114 AC: 3 AN: 2639

East Asian (EAS) AF: 0.00 AC: 0 AN: 3547

South Asian (SAS) AF: 0.00560 AC: 15 AN: 2678

European-Finnish (FIN) AF: 0.00823 AC: 49 AN: 5956

Middle Eastern (MID) AF: 0.0139 AC: 3 AN: 216

European-Non Finnish (NFE) AF: 0.00703 AC: 373 AN: 53056

Other (OTH) AF: 0.00595 AC: 9 AN: 1512

Alfa AF: 0.00593 Hom.: 279

Bravo AF: 0.00373

TwinsUK AF: 0.00674 AC: 25

ALSPAC AF: 0.00865 AC: 25

ESP6500AA AF: 0.00104 AC: 4

ESP6500EA AF: 0.00624 AC: 42

ExAC AF: 0.00466 AC: 566

EpiCase AF: 0.00638

EpiControl AF: 0.00741

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.48
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.16	T
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Pathogenic	0.98	D
MetaRNN	Benign	0.0070	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
PhyloP100		3.4
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.74	N
REVEL	Benign	0.11
Sift	Benign	0.063	T
Sift4G	Benign	0.46	T
Polyphen		1.0	D
Vest4		0.37
MVP		0.74
MPC		1.1
ClinPred		0.013	T
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.47
gMVP		0.12
Mutation Taster		=95/5	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs142403021; hg19: chrX-19555842; COSMIC: COSV65647139;