Genetic Variant SH3BGRL3:p.Ser22Thr (chr1-26280781-G-C) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_031286.4(SH3BGRL3):c.65G>C(p.Ser22Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,812 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

SH3BGRL3
NM_031286.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.83

Variant links:

Genes affected

SH3BGRL3 (HGNC:15568): (SH3 domain binding glutamate rich protein like 3) Located in nuclear body. [provided by Alliance of Genome Resources, Apr 2022]

SH3BGRL3 links:

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ACMG classification

Classification made for transcript

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=0.39564478).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SH3BGRL3	NM_031286.4 link	c.65G>C	p.Ser22Thr	missense_variant	Exon 2 of 3	ENST00000270792.10	NP_112576.1	Q9H299

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SH3BGRL3	ENST00000270792.10 link	c.65G>C	p.Ser22Thr	missense_variant	Exon 2 of 3	1	NM_031286.4	ENSP00000270792.5		Q9H299
SH3BGRL3	ENST00000319041.6 link	c.65G>C	p.Ser22Thr	missense_variant	Exon 2 of 2	2		ENSP00000363358.3		Q5T123

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251376

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135876

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS 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:

0.00000205

AC:

AN:

1461812

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727214

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 25, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.65G>C (p.S22T) alteration is located in exon 2 (coding exon 2) of the SH3BGRL3 gene. This alteration results from a G to C substitution at nucleotide position 65, causing the serine (S) at amino acid position 22 to be replaced by a threonine (T). 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

0.15

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Benign

-0.21

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.046

T;T

Eigen

Uncertain

0.37

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.78

T;T

M_CAP

Benign

0.082

MetaRNN

Benign

0.40

T;T

MetaSVM

Uncertain

-0.021

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-1.4

N;N

REVEL

Uncertain

0.36

Sift

Benign

0.098

T;T

Sift4G

Benign

0.29

T;T

Polyphen

0.28

B;.

Vest4

0.53

MutPred

0.60

Loss of disorder (P = 0.076);Loss of disorder (P = 0.076);

MVP

0.49

MPC

0.32

ClinPred

0.95

GERP RS

6.1

Varity_R

0.42

gMVP

0.43

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over