Genetic Variant SH3BP5L:p.Arg287Gln (chr1-248812222-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_030645.3(SH3BP5L):c.860G>A(p.Arg287Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SH3BP5L
NM_030645.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.640

Publications

0 publications found

Variant links:

Genes affected

SH3BP5L (HGNC:29360): (SH3 binding domain protein 5 like) Enables guanyl-nucleotide exchange factor activity. Predicted to be involved in intracellular signal transduction and negative regulation of protein tyrosine kinase activity. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

SH3BP5L links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06692156).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SH3BP5L	NM_030645.3 link	c.860G>A	p.Arg287Gln	missense_variant	Exon 7 of 7	ENST00000366472.6	NP_085148.1	Q7L8J4-1A0A024R0T2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SH3BP5L	ENST00000366472.6 link	c.860G>A	p.Arg287Gln	missense_variant	Exon 7 of 7	1	NM_030645.3	ENSP00000355428.5	Q7L8J4-1
SH3BP5L	ENST00000475978.1 link	n.2352G>A		non_coding_transcript_exon_variant	Exon 9 of 9	2
SH3BP5L	ENST00000484202.2 link	n.1334G>A		non_coding_transcript_exon_variant	Exon 2 of 2	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1455044

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

723870

African (AFR)

AF:

0.00

AC:

AN:

33424

American (AMR)

AF:

0.00

AC:

AN:

44364

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25786

East Asian (EAS)

AF:

0.00

AC:

AN:

39618

South Asian (SAS)

AF:

0.00

AC:

AN:

85822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50188

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1109886

Other (OTH)

AF:

0.00

AC:

AN:

60204

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 04, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.860G>A (p.R287Q) alteration is located in exon 7 (coding exon 6) of the SH3BP5L gene. This alteration results from a G to A substitution at nucleotide position 860, causing the arginine (R) at amino acid position 287 to be replaced by a glutamine (Q). 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

0.095

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.54

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.033

Eigen

Benign

-0.83

Eigen_PC

Benign

-0.77

FATHMM_MKL

Benign

0.29

LIST_S2

Benign

0.75

M_CAP

Benign

0.012

MetaRNN

Benign

0.067

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.69

PhyloP100

0.64

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-0.27

REVEL

Benign

0.043

Sift

Benign

0.15

Sift4G

Benign

0.14

Polyphen

0.30

Vest4

0.060

MutPred

0.41

Loss of glycosylation at P286 (P = 0.0667);

MVP

0.13

MPC

0.57

ClinPred

0.19

GERP RS

2.4

Varity_R

0.042

gMVP

0.29

Mutation Taster

=91/9

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over