3-15269762-C-T

Position:

• chr3-15269762-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_004844.5(SH3BP5):​c.446G>A​(p.Arg149Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000343 in 1,459,720 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R149W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: SH3BP5 NM_004844.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.80

Genes affected

SH3BP5 (HGNC:10827): (SH3 domain binding protein 5) Enables guanyl-nucleotide exchange factor activity and protein kinase inhibitor activity. Acts upstream of or within intracellular signal transduction. Located in cytoplasmic vesicle membrane and nuclear body. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SH3BP5	NM_004844.5	c.446G>A	p.Arg149Gln	missense_variant	4/9	ENST00000383791.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SH3BP5	ENST00000383791.8	c.446G>A	p.Arg149Gln	missense_variant	4/9	1	NM_004844.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000802 AC: 2 AN: 249406 Hom.: 0 AF XY: 0.00000741 AC XY: 1 AN XY: 134884

Gnomad AFR exome AF: 0.0000617

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000328

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000343 AC: 5 AN: 1459720 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 726044

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000384

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000165 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Benign	0.0058	T
BayesDel_noAF	Uncertain	-0.050
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.17	T
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Benign	0.68	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Uncertain	0.16	D
MetaRNN	Uncertain	0.74	D
MetaSVM	Uncertain	0.20	D
MutationAssessor	Uncertain	2.1	M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.58
Sift	Benign	0.10	T
Sift4G	Benign	0.16	T
Polyphen		0.98	D
Vest4		0.81
MutPred		0.49		Loss of MoRF binding (P = 0.0473);
MVP		0.92
MPC		1.7
ClinPred		0.56	D
GERP RS		5.9
Varity_R		0.62
gMVP		0.56

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

Publications

LitVar

Other links and lift over

dbSNP: rs764013758; hg19: chr3-15311269;