Genetic Variant SH3BP5L:p.Arg274Gly (chr1-248812262-G-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_030645.3(SH3BP5L):c.820C>G(p.Arg274Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0000247 in 1,459,668 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

SH3BP5L
NM_030645.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.86

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: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SH3BP5L	NM_030645.3 link	c.820C>G	p.Arg274Gly	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.820C>G	p.Arg274Gly	missense_variant	Exon 7 of 7	1	NM_030645.3	ENSP00000355428.5	Q7L8J4-1
SH3BP5L	ENST00000475978.1 link	n.2312C>G		non_coding_transcript_exon_variant	Exon 9 of 9	2
SH3BP5L	ENST00000484202.2 link	n.1294C>G		non_coding_transcript_exon_variant	Exon 2 of 2	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000161

AC:

AN:

247844

AF XY:

0.00000744

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000266

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.0000247

AC:

AN:

1459668

Hom.:

Cov.:

AF XY:

0.0000317

AC XY:

AN XY:

726226

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33474

American (AMR)

AF:

0.00

AC:

AN:

44680

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26106

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86238

European-Finnish (FIN)

AF:

0.0000194

AC:

AN:

51474

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0000315

AC:

AN:

1111866

Other (OTH)

AF:

0.00

AC:

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 08, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.820C>G (p.R274G) alteration is located in exon 7 (coding exon 6) of the SH3BP5L gene. This alteration results from a C to G substitution at nucleotide position 820, causing the arginine (R) at amino acid position 274 to be replaced by a glycine (G). 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

Uncertain

0.43

BayesDel_addAF

Benign

-0.057

BayesDel_noAF

Benign

-0.21

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.39

Eigen

Benign

-0.22

Eigen_PC

Benign

-0.33

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.86

M_CAP

Benign

0.019

MetaRNN

Uncertain

0.49

MetaSVM

Benign

-0.89

MutationAssessor

Benign

2.0

PhyloP100

4.9

PrimateAI

Pathogenic

0.89

PROVEAN

Uncertain

-3.4

REVEL

Benign

0.24

Sift

Uncertain

0.0050

Sift4G

Uncertain

0.016

Polyphen

0.81

Vest4

0.43

MutPred

0.62

Gain of loop (P = 0.0045);

MVP

0.31

MPC

1.3

ClinPred

0.70

GERP RS

1.3

Varity_R

0.34

gMVP

0.35

Mutation Taster

=81/19

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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1-248812262-G-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over