Genetic Variant SH3BP5L:p.Gly381Arg (chr1-248811941-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_030645.3(SH3BP5L):c.1141G>A(p.Gly381Arg) 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: 0.347

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.14401287).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SH3BP5L	NM_030645.3 link	c.1141G>A	p.Gly381Arg	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.1141G>A	p.Gly381Arg	missense_variant	Exon 7 of 7	1	NM_030645.3	ENSP00000355428.5	Q7L8J4-1
SH3BP5L	ENST00000475978.1 link	n.2633G>A		non_coding_transcript_exon_variant	Exon 9 of 9	2
SH3BP5L	ENST00000484202.2 link	n.1615G>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:

1404994

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

693336

African (AFR)

AF:

0.00

AC:

AN:

32402

American (AMR)

AF:

0.00

AC:

AN:

36162

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25074

East Asian (EAS)

AF:

0.00

AC:

AN:

37038

South Asian (SAS)

AF:

0.00

AC:

AN:

80280

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48230

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4828

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1082836

Other (OTH)

AF:

0.00

AC:

AN:

58144

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

Jul 12, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1141G>A (p.G381R) 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 1141, causing the glycine (G) at amino acid position 381 to be replaced by an arginine (R). 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

0.11

BayesDel_addAF

Benign

-0.060

BayesDel_noAF

Benign

-0.32

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.029

Eigen

Benign

-0.30

Eigen_PC

Benign

-0.43

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.57

M_CAP

Benign

0.014

MetaRNN

Benign

0.14

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.34

PhyloP100

0.35

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-0.080

REVEL

Benign

0.13

Sift

Uncertain

0.0070

Sift4G

Uncertain

0.052

Polyphen

0.99

Vest4

0.14

MutPred

0.21

Gain of methylation at G381 (P = 0.0087);

MVP

0.29

MPC

0.82

ClinPred

0.35

GERP RS

3.6

Varity_R

0.085

gMVP

0.11

Mutation Taster

=84/16

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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