rs7823

Positions:

• chr5-54456158-T-C
• chr5-54456158-T-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_006308.3(HSPB3):​c.369T>C​(p.Gly123Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.61 in 1,613,514 control chromosomes in the GnomAD database, including 303,229 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.63 (30948 hom., cov: 31)
  • Exomes 𝑓: 0.61 (272281 hom.)
• Consequence: HSPB3 NM_006308.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -1.12

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 5-54456158-T-C is Benign according to our data. Variant chr5-54456158-T-C is described in ClinVar as [Benign]. Clinvar id is 353903.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-54456158-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.12 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.727 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HSPB3	NM_006308.3	c.369T>C	p.Gly123Gly	synonymous_variant	1/1	ENST00000302005.3	NP_006299.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HSPB3	ENST00000302005.3	c.369T>C	p.Gly123Gly	synonymous_variant	1/1	6	NM_006308.3	ENSP00000303394.1

Frequencies

GnomAD3 genomes AF: 0.631 AC: 95888 AN: 151888 Hom.: 30912 Cov.: 31

Gnomad AFR AF: 0.734

Gnomad AMI AF: 0.718

Gnomad AMR AF: 0.513

Gnomad ASJ AF: 0.590

Gnomad EAS AF: 0.358

Gnomad SAS AF: 0.565

Gnomad FIN AF: 0.627

Gnomad MID AF: 0.677

Gnomad NFE AF: 0.622

Gnomad OTH AF: 0.631

GnomAD3 exomes AF: 0.585 AC: 147027 AN: 251424 Hom.: 44219 AF XY: 0.587 AC XY: 79801 AN XY: 135886

Gnomad AFR exome AF: 0.741

Gnomad AMR exome AF: 0.479

Gnomad ASJ exome AF: 0.597

Gnomad EAS exome AF: 0.357

Gnomad SAS exome AF: 0.571

Gnomad FIN exome AF: 0.626

Gnomad NFE exome AF: 0.625

Gnomad OTH exome AF: 0.611

GnomAD4 exome AF: 0.607 AC: 887491 AN: 1461508 Hom.: 272281 Cov.: 49 AF XY: 0.606 AC XY: 440768 AN XY: 727102

Gnomad4 AFR exome AF: 0.744

Gnomad4 AMR exome AF: 0.480

Gnomad4 ASJ exome AF: 0.593

Gnomad4 EAS exome AF: 0.347

Gnomad4 SAS exome AF: 0.571

Gnomad4 FIN exome AF: 0.628

Gnomad4 NFE exome AF: 0.619

Gnomad4 OTH exome AF: 0.613

GnomAD4 genome AF: 0.631 AC: 95978 AN: 152006 Hom.: 30948 Cov.: 31 AF XY: 0.626 AC XY: 46473 AN XY: 74294

Gnomad4 AFR AF: 0.734

Gnomad4 AMR AF: 0.513

Gnomad4 ASJ AF: 0.590

Gnomad4 EAS AF: 0.358

Gnomad4 SAS AF: 0.565

Gnomad4 FIN AF: 0.627

Gnomad4 NFE AF: 0.622

Gnomad4 OTH AF: 0.634

Alfa AF: 0.621 Hom.: 38772

Bravo AF: 0.629

Asia WGS AF: 0.481 AC: 1671 AN: 3478

EpiCase AF: 0.625

EpiControl AF: 0.631

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neuronopathy, distal hereditary motor, type 2C Benign:4

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 16, 2017	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	2.3
DANN	Benign	0.38

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs7823; hg19: chr5-53751988; COSMIC: COSV57356586;