21-39499830-A-G

Variant names:

• chr21-39499830-A-G
• NM_007341.3:c.320A>G

Variant summary

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

The NM_007341.3(SH3BGR):​c.320A>G​(p.Glu107Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SH3BGR NM_007341.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.97
• Publications: 0 publications found

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]

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]

ACMG classification

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	c.320A>G	p.Glu107Gly	missense_variant	Exon 4 of 7	ENST00000333634.10	NP_031367.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SH3BGR	ENST00000333634.10	c.320A>G	p.Glu107Gly	missense_variant	Exon 4 of 7	1	NM_007341.3	ENSP00000332513.5
GET1-SH3BGR	ENST00000647779.1	c.611A>G	p.Glu204Gly	missense_variant	Exon 6 of 9			ENSP00000497977.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 05, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.509A>G (p.E170G) alteration is located in exon 4 (coding exon 4) of the SH3BGR gene. This alteration results from a A to G substitution at nucleotide position 509, causing the glutamic acid (E) at amino acid position 170 to be replaced by a glycine (G). 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	0.080
BayesDel_addAF	Uncertain	0.014	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	23
DANN	Benign	0.88
DEOGEN2	Benign	0.11	.;.;.;T;.;T;T;T
Eigen	Uncertain	0.21
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.38	T;.;.;T;T;T;T;T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.26	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.63	T
MutationAssessor	Uncertain	2.7	.;.;.;.;.;M;.;.
PhyloP100		4.0
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-2.8	.;D;D;D;D;D;D;D
REVEL	Benign	0.18
Sift	Uncertain	0.0030	.;D;D;D;D;D;D;.
Sift4G	Uncertain	0.0090	.;D;D;D;D;D;D;D
Polyphen		0.91	.;.;.;.;.;P;.;.
Vest4		0.26, 0.27
MutPred		0.16		.;.;.;.;.;Gain of loop (P = 0.0312);.;.;
MVP		0.53
MPC		0.37
ClinPred		0.82	D
GERP RS		5.0
PromoterAI		-0.024	Neutral
Varity_R		0.17
gMVP		0.45
Mutation Taster		=79/21	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.48		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.48		Position offset: -7

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

hg19: chr21-40871756;