rs7699

chr5-54456071-G-Achr5-54456071-G-C

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.282G>A(p.Leu94=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.576 in 1,613,562 control chromosomes in the GnomAD database, including 271,020 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.54 (22442 hom., cov: 30)
  • Exomes 𝑓: 0.58 (248578 hom.)
• Consequence: HSPB3 NM_006308.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.532

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=-0.49).
• BP6: Variant 5-54456071-G-A is Benign according to our data. Variant chr5-54456071-G-A is described in ClinVar as [Benign]. Clinvar id is 353899.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-54456071-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.532 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.598 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HSPB3	NM_006308.3	c.282G>A	p.Leu94=	synonymous_variant	1/1	ENST00000302005.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HSPB3	ENST00000302005.3	c.282G>A	p.Leu94=	synonymous_variant	1/1		NM_006308.3	P1

Frequencies

GnomAD3 genomes AF: 0.537 AC: 81554 AN: 151744 Hom.: 22437 Cov.: 30

Gnomad AFR AF: 0.444

Gnomad AMI AF: 0.715

Gnomad AMR AF: 0.475

Gnomad ASJ AF: 0.605

Gnomad EAS AF: 0.355

Gnomad SAS AF: 0.553

Gnomad FIN AF: 0.613

Gnomad MID AF: 0.659

Gnomad NFE AF: 0.602

Gnomad OTH AF: 0.551

GnomAD3 exomes AF: 0.552 AC: 138678 AN: 251306 Hom.: 39293 AF XY: 0.560 AC XY: 76044 AN XY: 135804

Gnomad AFR exome AF: 0.449

Gnomad AMR exome AF: 0.460

Gnomad ASJ exome AF: 0.607

Gnomad EAS exome AF: 0.352

Gnomad SAS exome AF: 0.554

Gnomad FIN exome AF: 0.614

Gnomad NFE exome AF: 0.607

Gnomad OTH exome AF: 0.591

GnomAD4 exome AF: 0.580 AC: 848070 AN: 1461700 Hom.: 248578 Cov.: 62 AF XY: 0.581 AC XY: 422144 AN XY: 727168

Gnomad4 AFR exome AF: 0.445

Gnomad4 AMR exome AF: 0.459

Gnomad4 ASJ exome AF: 0.602

Gnomad4 EAS exome AF: 0.345

Gnomad4 SAS exome AF: 0.554

Gnomad4 FIN exome AF: 0.616

Gnomad4 NFE exome AF: 0.597

Gnomad4 OTH exome AF: 0.576

GnomAD4 genome AF: 0.537 AC: 81595 AN: 151862 Hom.: 22442 Cov.: 30 AF XY: 0.534 AC XY: 39611 AN XY: 74196

Gnomad4 AFR AF: 0.444

Gnomad4 AMR AF: 0.475

Gnomad4 ASJ AF: 0.605

Gnomad4 EAS AF: 0.355

Gnomad4 SAS AF: 0.553

Gnomad4 FIN AF: 0.613

Gnomad4 NFE AF: 0.602

Gnomad4 OTH AF: 0.555

Alfa AF: 0.575 Hom.: 18633

Bravo AF: 0.525

Asia WGS AF: 0.455 AC: 1579 AN: 3478

EpiCase AF: 0.606

EpiControl AF: 0.613

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

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+	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 16, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
Cadd	Benign	11
Dann	Benign	0.79

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: rs7699; hg19: chr5-53751901; COSMIC: COSV57356747;