Variant chr19-4362687-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_003025.4(SH3GL1):c.778C>T(p.Arg260Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000291 in 1,613,878 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

SH3GL1
NM_003025.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.10

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

High AC in GnomAd4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SH3GL1	NM_003025.4 linkuse as main transcript	c.778C>T	p.Arg260Trp	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.778C>T	p.Arg260Trp	missense_variant	8/10	1	NM_003025.4	ENSP00000269886.2	Q99961-1
SH3GL1	ENST00000417295.6 linkuse as main transcript	c.634C>T	p.Arg212Trp	missense_variant	7/9	2		ENSP00000404568.2	Q99961-2
SH3GL1	ENST00000598564.5 linkuse as main transcript	c.586C>T	p.Arg196Trp	missense_variant	8/10	2		ENSP00000470792.1	Q99961-3

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152236

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000578

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000358

AC:

AN:

251310

Hom.:

AF XY:

0.0000294

AC XY:

AN XY:

135850

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000253

AC:

AN:

1461642

Hom.:

Cov.:

AF XY:

0.0000248

AC XY:

AN XY:

727128

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000227

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000162

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000657

AC:

AN:

152236

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74368

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000578

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000831

ExAC

AF:

0.0000494

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

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

Dec 17, 2023

The c.778C>T (p.R260W) alteration is located in exon 8 (coding exon 8) of the SH3GL1 gene. This alteration results from a C to T substitution at nucleotide position 778, causing the arginine (R) at amino acid position 260 to be replaced by a tryptophan (W). 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

0.19

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.33

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.22

T;.;.

Eigen

Uncertain

0.27

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.82

T;T;T

M_CAP

Benign

0.042

MetaRNN

Uncertain

0.45

T;T;T

MetaSVM

Benign

-0.88

MutationAssessor

Uncertain

2.4

M;.;.

PrimateAI

Benign

0.48

PROVEAN

Uncertain

-3.6

D;.;D

REVEL

Benign

0.10

Sift

Uncertain

0.028

D;.;D

Sift4G

Benign

0.093

T;T;T

Polyphen

0.95

P;.;.

Vest4

0.61

MutPred

0.28

Gain of methylation at K256 (P = 0.0395);.;.;

MVP

0.64

MPC

0.40

ClinPred

0.46

GERP RS

3.7

Varity_R

0.25

gMVP

0.44

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