chr21-39499871-G-T

Variant names:

• chr21-39499871-G-T
• rs147131543
• NM_007341.3:c.361G>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_007341.3(SH3BGR):​c.361G>T​(p.Gly121Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000374 in 1,613,918 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. 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. G121S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0022 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00019 (2 hom.)
• Consequence: SH3BGR NM_007341.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.91
• 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0036056936).
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SH3BGR	NM_007341.3	c.361G>T	p.Gly121Cys	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.361G>T	p.Gly121Cys	missense_variant	Exon 4 of 7	1	NM_007341.3	ENSP00000332513.5
GET1-SH3BGR	ENST00000647779.1	c.652G>T	p.Gly218Cys	missense_variant	Exon 6 of 9			ENSP00000497977.1

Frequencies

GnomAD3 genomes AF: 0.00216 AC: 329 AN: 152046 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00778

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000961

GnomAD2 exomes AF: 0.000541 AC: 136 AN: 251450 AF XY: 0.000375

Gnomad AFR exome AF: 0.00775

Gnomad AMR exome AF: 0.000260

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000188 AC: 275 AN: 1461754 Hom.: 2 Cov.: 30 AF XY: 0.000164 AC XY: 119 AN XY: 727184

African (AFR) AF: 0.00744 AC: 249 AN: 33476

American (AMR) AF: 0.000246 AC: 11 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111922

Other (OTH) AF: 0.000232 AC: 14 AN: 60388

GnomAD4 genome AF: 0.00216 AC: 329 AN: 152164 Hom.: 1 Cov.: 32 AF XY: 0.00198 AC XY: 147 AN XY: 74390

African (AFR) AF: 0.00776 AC: 322 AN: 41514

American (AMR) AF: 0.000262 AC: 4 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67994

Other (OTH) AF: 0.000951 AC: 2 AN: 2104

Alfa AF: 0.000868 Hom.: 0

Bravo AF: 0.00203

ESP6500AA AF: 0.00794 AC: 35

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000651 AC: 79

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	21
DANN	Benign	0.48
DEOGEN2	Benign	0.025	.;.;.;T;.;T;T;T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.64	T;.;.;T;T;T;T;T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.0036	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.81	.;.;.;.;.;L;.;.
PhyloP100		1.9
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.6	.;N;N;N;N;N;D;D
REVEL	Benign	0.10
Sift	Uncertain	0.011	.;D;D;D;D;D;D;.
Sift4G	Uncertain	0.025	.;D;D;D;D;D;D;D
Polyphen		0.97	.;.;.;.;.;D;.;.
Vest4		0.23, 0.21
MVP		0.18
MPC		0.14
ClinPred		0.027	T
GERP RS		3.1
PromoterAI		-0.0064	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.16
gMVP		0.45
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs147131543; hg19: chr21-40871797;