chr3-15262249-A-G

Position:

• chr3-15262249-A-G

Variant summary

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

The NM_004844.5(SH3BP5):​c.536T>C​(p.Val179Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SH3BP5 NM_004844.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.09

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]

SH3BP5-AS1 (HGNC:44501): (SH3BP5 antisense RNA 1)

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.536T>C	p.Val179Ala	missense_variant	5/9	ENST00000383791.8
SH3BP5-AS1	NR_046084.1	n.5372+1667A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SH3BP5	ENST00000383791.8	c.536T>C	p.Val179Ala	missense_variant	5/9	1	NM_004844.5	P1
SH3BP5-AS1	ENST00000420195.1	n.5372+1667A>G		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 12, 2023

The c.536T>C (p.V179A) alteration is located in exon 5 (coding exon 5) of the SH3BP5 gene. This alteration results from a T to C substitution at nucleotide position 536, causing the valine (V) at amino acid position 179 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T;.;.;T;.
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.86	D;.;D;T;T
M_CAP	Benign	0.033	D
MetaRNN	Uncertain	0.59	D;D;D;D;D
MetaSVM	Benign	-0.53	T
MutationAssessor	Benign	1.2	L;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-0.35	N;N;N;N;N
REVEL	Benign	0.18
Sift	Benign	0.56	T;T;T;T;T
Sift4G	Benign	0.84	T;T;T;T;T
Polyphen		0.68	P;.;.;.;.
Vest4		0.45
MutPred		0.52		Loss of stability (P = 0.0081);.;.;.;.;
MVP		0.85
MPC		1.8
ClinPred		0.75	D
GERP RS		5.8
Varity_R		0.28
gMVP		0.30

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: rs1575280851; hg19: chr3-15303756; COSMIC: COSV53745856; COSMIC: COSV53745856;