Genetic Variant SH3GL3:p.Ser281Pro (chr15-83618084-T-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_003027.5(SH3GL3):c.841T>C(p.Ser281Pro) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,455,618 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

SH3GL3
NM_003027.5 missense, splice_region

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.681

Publications

0 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.063117266).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003027.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SH3GL3	NM_003027.5	MANE Select	c.841T>C	p.Ser281Pro	missense splice_region	Exon 9 of 9	NP_003018.3
SH3GL3	NM_001301109.2		c.865T>C	p.Ser289Pro	missense splice_region	Exon 12 of 12	NP_001288038.1	Q99963-3
SH3GL3	NM_001324183.2		c.865T>C	p.Ser289Pro	missense splice_region	Exon 10 of 10	NP_001311112.1	Q99963-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SH3GL3	ENST00000427482.7	TSL:1 MANE Select	c.841T>C	p.Ser281Pro	missense splice_region	Exon 9 of 9	ENSP00000391372.2	Q99963-1
SH3GL3	ENST00000563901.5	TSL:1	n.*636T>C		splice_region non_coding_transcript_exon	Exon 9 of 9	ENSP00000456249.1	H3BRH8
SH3GL3	ENST00000563901.5	TSL:1	n.*636T>C		3_prime_UTR	Exon 9 of 9	ENSP00000456249.1	H3BRH8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.87e-7

AC:

AN:

1455618

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

724654

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33326

American (AMR)

AF:

0.00

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26100

East Asian (EAS)

AF:

0.00

AC:

AN:

39662

South Asian (SAS)

AF:

0.00

AC:

AN:

86138

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

9.04e-7

AC:

AN:

1106286

Other (OTH)

AF:

0.00

AC:

AN:

60210

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.70

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.012

Eigen

Benign

-0.55

Eigen_PC

Benign

-0.50

FATHMM_MKL

Uncertain

0.78

LIST_S2

Benign

0.41

M_CAP

Benign

0.0068

MetaRNN

Benign

0.063

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.2

PhyloP100

0.68

PrimateAI

Benign

0.32

PROVEAN

Benign

0.10

REVEL

Benign

0.073

Sift

Benign

0.33

Sift4G

Benign

0.31

Polyphen

0.60

Vest4

0.051

MutPred

0.31

Loss of glycosylation at S281 (P = 0.0375)

MVP

0.34

MPC

0.53

ClinPred

0.28

GERP RS

-1.6

Varity_R

0.060

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over