Variant 19-4362620-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_003025.4(SH3GL1):c.845A>G(p.Lys282Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000958 in 1,461,358 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

SH3GL1
NM_003025.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.45

Variant links:

Genes affected

SH3GL1 (HGNC:10830): (SH3 domain containing GRB2 like 1, endophilin A2) This gene encodes a member of the endophilin family of Src homology 3 domain-containing proteins. The encoded protein is involved in endocytosis and may also play a role in the cell cycle. Overexpression of this gene may play a role in leukemogenesis, and the encoded protein has been implicated in acute myeloid leukemia as a fusion partner of the myeloid-lymphoid leukemia protein. Pseudogenes of this gene are located on the long arm of chromosomes 11 and 17. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Jan 2011]

SH3GL1 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.12218639).

BS2

High AC in GnomAdExome4 at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SH3GL1	NM_003025.4 linkuse as main transcript	c.845A>G	p.Lys282Arg	missense_variant	8/10	ENST00000269886.7	NP_003016.1	Q99961-1Q6FGM0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
SH3GL1	ENST00000269886.7 linkuse as main transcript	c.845A>G	p.Lys282Arg	missense_variant	8/10	1	NM_003025.4	ENSP00000269886.2	Q99961-1
SH3GL1	ENST00000417295.6 linkuse as main transcript	c.701A>G	p.Lys234Arg	missense_variant	7/9	2		ENSP00000404568.2	Q99961-2
SH3GL1	ENST00000598564.5 linkuse as main transcript	c.653A>G	p.Lys218Arg	missense_variant	8/10	2		ENSP00000470792.1	Q99961-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000797

AC:

AN:

250954

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135748

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 SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000958

AC:

AN:

1461358

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

726984

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000139

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.0000166

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 16, 2023

The c.845A>G (p.K282R) alteration is located in exon 8 (coding exon 8) of the SH3GL1 gene. This alteration results from a A to G substitution at nucleotide position 845, causing the lysine (K) at amino acid position 282 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

0.069

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.58

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.026

T;.;.

Eigen

Benign

-0.27

Eigen_PC

Benign

-0.20

FATHMM_MKL

Benign

0.66

LIST_S2

Benign

0.83

T;T;T

M_CAP

Benign

0.016

MetaRNN

Benign

0.12

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.6

L;.;.

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-0.71

N;.;N

REVEL

Benign

0.064

Sift

Benign

0.32

T;.;T

Sift4G

Benign

0.36

T;T;T

Polyphen

0.14

B;.;.

Vest4

0.41

MutPred

0.32

Loss of ubiquitination at K282 (P = 0.0074);.;.;

MVP

0.51

MPC

0.38

ClinPred

0.21

GERP RS

3.8

Varity_R

0.084

gMVP

0.26

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over