Variant 15-83618221-G-T 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_003027.5(SH3GL3):c.978G>T(p.Met326Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000676 in 1,611,778 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 𝑓 0.000059 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000069 ( 0 hom. )

Consequence

SH3GL3
NM_003027.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.01

Variant links:

Genes affected

SH3GL3 (HGNC:10832): (SH3 domain containing GRB2 like 3, endophilin A3) Enables identical protein binding activity. Predicted to be involved in synaptic vesicle uncoating. Predicted to be located in acrosomal vesicle; early endosome membrane; and presynapse. Predicted to be part of early endosome. Predicted to be active in glutamatergic synapse; postsynaptic density, intracellular component; and postsynaptic endosome. [provided by Alliance of Genome Resources, Apr 2022]

SH3GL3 links:

SH3GL3 (HGNC:):

SH3GL3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.1262142).

BS2

High AC in GnomAd4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SH3GL3	NM_003027.5 linkuse as main transcript	c.978G>T	p.Met326Ile	missense_variant	9/9	ENST00000427482.7	NP_003018.3	Q99963-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SH3GL3	ENST00000427482.7 linkuse as main transcript	c.978G>T	p.Met326Ile	missense_variant	9/9	1	NM_003027.5	ENSP00000391372.2		Q99963-1

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152196

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:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000795

AC:

AN:

251472

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135910

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000685

AC:

100

AN:

1459582

Hom.:

Cov.:

AF XY:

0.0000757

AC XY:

AN XY:

726318

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:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000838

Gnomad4 OTH exome

AF:

0.0000994

GnomAD4 genome

AF:

0.0000591

AC:

AN:

152196

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000579

Hom.:

Bravo

AF:

0.0000680

ExAC

AF:

0.00000824

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

Nov 18, 2022

The c.978G>T (p.M326I) alteration is located in exon 9 (coding exon 9) of the SH3GL3 gene. This alteration results from a G to T substitution at nucleotide position 978, causing the methionine (M) at amino acid position 326 to be replaced by an isoleucine (I). 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

0.20

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.53

CADD

Benign

DANN

Benign

0.90

DEOGEN2

Benign

0.050

T;.

Eigen

Benign

-0.73

Eigen_PC

Benign

-0.65

FATHMM_MKL

Benign

0.67

LIST_S2

Benign

0.76

T;T

M_CAP

Benign

0.0096

MetaRNN

Benign

0.13

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.065

N;.

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-2.1

N;N

REVEL

Benign

0.17

Sift

Benign

0.28

T;T

Sift4G

Benign

0.28

T;T

Polyphen

0.0

B;B

Vest4

0.20

MutPred

0.36

Gain of sheet (P = 0.1208);.;

MVP

0.52

MPC

0.46

ClinPred

0.098

GERP RS

-2.4

Varity_R

0.14

gMVP

0.42

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