chr5-54455983-G-A

Variant names:

• chr5-54455983-G-A
• rs371683736
• NM_006308.3:c.194G>A

Variant summary

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

The NM_006308.3(HSPB3):​c.194G>A​(p.Arg65Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000889 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 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: 0.0000089 (0 hom.)
• Consequence: HSPB3 NM_006308.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.219
• Publications: 3 publications found

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 Gene-Disease associations (from GenCC):

• distal hereditary motor neuropathy type 2

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• neuronopathy, distal hereditary motor, type 2C

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.04929006).
• BS2: High AC in GnomAdExome4 at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSPB3	NM_006308.3	c.194G>A	p.Arg65Gln	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.194G>A	p.Arg65Gln	missense_variant	Exon 1 of 1	6	NM_006308.3	ENSP00000303394.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251066 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000889 AC: 13 AN: 1461886 Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9 AN XY: 727244

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000927 AC: 8 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112010

Other (OTH) AF: 0.0000497 AC: 3 AN: 60394

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000165 AC: 2

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Jul 20, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine with glutamine at codon 65 of the HSPB3 protein (p.Arg65Gln). The arginine residue is weakly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs371683736, ExAC 0.01%). This variant has not been reported in the literature in individuals with HSPB3-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glutamine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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	0.061
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	1.0
DANN	Benign	0.86
DEOGEN2	Benign	0.050	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.062	D
MetaRNN	Benign	0.049	T
MetaSVM	Benign	-0.53	T
MutationAssessor	Benign	-0.26	N
PhyloP100		-0.22
PrimateAI	Benign	0.20	T
PROVEAN	Benign	0.21	N
REVEL	Benign	0.20
Sift	Benign	0.90	T
Sift4G	Benign	0.83	T
Polyphen		0.0	B
Vest4		0.036
MutPred		0.46		Gain of ubiquitination at K68 (P = 0.0561);
MVP		0.51
MPC		0.10
ClinPred		0.023	T
GERP RS		-8.6
PromoterAI		-0.069	Neutral
Varity_R		0.033
gMVP		0.13
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs371683736; hg19: chr5-53751813; COSMIC: COSV57356612;