5-54455915-C-G

Variant names:

• chr5-54455915-C-G
• rs773913025
• NM_006308.3:c.126C>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006308.3(HSPB3):​c.126C>G​(p.Ile42Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: HSPB3 NM_006308.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.45

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14666268).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSPB3	NM_006308.3	c.126C>G	p.Ile42Met	missense_variant	Exon 1 of 1	ENST00000302005.3	NP_006299.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HSPB3	ENST00000302005.3	c.126C>G	p.Ile42Met	missense_variant	Exon 1 of 1	6	NM_006308.3	ENSP00000303394.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461892 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727246

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: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Neuronopathy, distal hereditary motor, type 2C Uncertain:1

Dec 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 42 of the HSPB3 protein (p.Ile42Met). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with HSPB3-related conditions. 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	0.070
BayesDel_addAF	Benign	-0.065	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	6.7
DANN	Benign	0.95
DEOGEN2	Benign	0.024	T
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.034	N
LIST_S2	Benign	0.59	T
M_CAP	Uncertain	0.088	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-0.30	T
MutationAssessor	Benign	2.0	M
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.010	N
REVEL	Uncertain	0.33
Sift	Benign	0.053	T
Sift4G	Benign	0.081	T
Polyphen		0.69	P
Vest4		0.084
MutPred		0.37		Gain of disorder (P = 0.0349);
MVP		0.64
MPC		0.17
ClinPred		0.14	T
GERP RS		-0.66
Varity_R		0.069
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

Other links and lift over

dbSNP: rs773913025; hg19: chr5-53751745;