Genetic Variant SH3BGR:p.Ile63Phe (chr21-39462516-A-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_007341.3(SH3BGR):c.187A>T(p.Ile63Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,453,638 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I63V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

SH3BGR
NM_007341.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 8.79

Publications

0 publications found

Variant links:

Genes affected

SH3BGR (HGNC:10822): (SH3 domain binding glutamate rich protein) Predicted to enable SH3 domain binding activity. Predicted to be involved in protein-containing complex assembly. Located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

SH3BGR links:

GET1-SH3BGR (HGNC:54635): (GET1-SH3BGR readthrough) This locus represents naturally occurring readthrough transcription between the neighboring WRB (tryptophan rich basic protein) and SH3BGR (SH3 domain binding glutamate-rich protein) genes on chromosome 21. Readthrough transcripts may encode fusion proteins that shares sequence identity with each individual gene product. [provided by RefSeq, Apr 2017]

GET1-SH3BGR links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SH3BGR	NM_007341.3 link	c.187A>T	p.Ile63Phe	missense_variant	Exon 2 of 7	ENST00000333634.10	NP_031367.2	P55822

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SH3BGR	ENST00000333634.10 link	c.187A>T	p.Ile63Phe	missense_variant	Exon 2 of 7	1	NM_007341.3	ENSP00000332513.5		A0A804CBI3
GET1-SH3BGR	ENST00000647779.1 link	c.478A>T	p.Ile160Phe	missense_variant	Exon 4 of 9			ENSP00000497977.1		A0A3B3ITX9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000414

AC:

AN:

241750

AF XY:

0.00000764

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.88e-7

AC:

AN:

1453638

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

723150

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32908

American (AMR)

AF:

0.00

AC:

AN:

41620

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25912

East Asian (EAS)

AF:

0.00

AC:

AN:

39506

South Asian (SAS)

AF:

0.0000119

AC:

AN:

84260

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53360

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5738

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1110268

Other (OTH)

AF:

0.00

AC:

AN:

60066

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.:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.82

BayesDel_addAF

Uncertain

0.060

BayesDel_noAF

Uncertain

-0.050

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.029

.;.;.;T;T;.;T

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

D;.;.;D;D;D;D

M_CAP

Benign

0.048

MetaRNN

Uncertain

0.49

T;T;T;T;T;T;T

MetaSVM

Benign

-0.29

MutationAssessor

Uncertain

2.1

.;.;.;.;.;.;M

PhyloP100

8.8

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

-1.9

.;N;N;N;N;N;N

REVEL

Uncertain

0.43

Sift

Benign

0.067

.;T;T;T;T;T;T

Sift4G

Benign

0.70

.;T;T;T;T;T;T

Polyphen

0.90

.;.;.;.;.;.;P

Vest4

0.73, 0.67, 0.61

MutPred

0.36

.;.;.;.;.;.;Gain of catalytic residue at I126 (P = 0.1105);

MVP

0.77

MPC

0.43

ClinPred

0.79

GERP RS

5.0

PromoterAI

-0.011

Neutral

(source)

Varity_R

0.36

gMVP

0.47

Mutation Taster

=35/65

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.14

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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over