chr21-39462549-C-A

Position:

• chr21-39462549-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_007341.3(SH3BGR):​c.220C>A​(p.Gln74Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict 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: 2.43

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

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26928967).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SH3BGR	NM_007341.3	c.220C>A	p.Gln74Lys	missense_variant	2/7	ENST00000333634.10	NP_031367.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SH3BGR	ENST00000333634.10	c.220C>A	p.Gln74Lys	missense_variant	2/7	1	NM_007341.3	ENSP00000332513.5
GET1-SH3BGR	ENST00000647779.1	c.511C>A	p.Gln171Lys	missense_variant	4/9			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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 14, 2024

The c.409C>A (p.Q137K) alteration is located in exon 2 (coding exon 2) of the SH3BGR gene. This alteration results from a C to A substitution at nucleotide position 409, causing the glutamine (Q) at amino acid position 137 to be replaced by a lysine (K). 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	0.14
BayesDel_addAF	Benign	-0.014	T
BayesDel_noAF	Benign	-0.26
CADD	Uncertain	25
DANN	Benign	0.95
DEOGEN2	Benign	0.031	.;.;.;T;T;.;T;T
Eigen	Benign	-0.14
Eigen_PC	Benign	0.057
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.86	D;.;.;D;D;D;D;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.27	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	1.2	.;.;.;.;.;.;L;.
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.4	.;N;N;N;N;N;N;N
REVEL	Benign	0.088
Sift	Benign	0.13	.;T;T;T;T;T;T;D
Sift4G	Benign	0.44	.;T;T;T;T;T;T;T
Polyphen		0.021	.;.;.;.;.;.;B;.
Vest4		0.22, 0.28, 0.26
MutPred		0.42		.;.;.;.;.;.;Gain of methylation at Q137 (P = 0.0059);.;
MVP		0.30
MPC		0.12
ClinPred		0.64	D
GERP RS		5.0
Varity_R		0.31
gMVP		0.40

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr21-40834475;