Variant 5-54455857-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_006308.3(HSPB3):c.68G>A(p.Arg23Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000013 in 1,461,874 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: 32)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

HSPB3
NM_006308.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 5.76

Variant links:

Genes affected

HSPB3 (HGNC:5248): (heat shock protein family B (small) member 3) This gene encodes a muscle-specific small heat shock protein. A mutation in this gene is the cause of autosomal dominant distal hereditary motor neuropathy type 2C.[provided by RefSeq, Sep 2010]

HSPB3 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.20250538).

BS2

High AC in GnomAdExome4 at 19 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HSPB3	NM_006308.3 linkuse as main transcript	c.68G>A	p.Arg23Gln	missense_variant	1/1	ENST00000302005.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HSPB3	ENST00000302005.3 linkuse as main transcript	c.68G>A	p.Arg23Gln	missense_variant	1/1		NM_006308.3	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

251174

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135740

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000130

AC:

AN:

1461874

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000374

Gnomad4 NFE exome

AF:

0.0000153

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000413

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Neuronopathy, distal hereditary motor, type 2C

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Sep 12, 2019	This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: BP4. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 20, 2024	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 23 of the HSPB3 protein (p.Arg23Gln). This variant is present in population databases (rs780119257, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with HSPB3-related conditions. ClinVar contains an entry for this variant (Variation ID: 931148). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.096

BayesDel_addAF

Benign

-0.023

BayesDel_noAF

Benign

-0.16

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.038

Eigen

Uncertain

0.27

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Benign

0.75

LIST_S2

Benign

0.79

M_CAP

Benign

0.028

MetaRNN

Benign

0.20

MetaSVM

Uncertain

0.27

MutationAssessor

Uncertain

2.2

MutationTaster

Benign

0.79

PrimateAI

Benign

0.41

PROVEAN

Benign

-1.1

REVEL

Uncertain

0.42

Sift

Benign

0.065

Sift4G

Benign

0.13

Polyphen

0.47

Vest4

0.063

MVP

0.73

MPC

0.15

ClinPred

0.33

GERP RS

6.0

Varity_R

0.094

gMVP

0.37

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