rs7699

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_006308.3(HSPB3):c.282G>A(p.Leu94Leu) 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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 0.532

Publications

20 publications found

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 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)

HSPB3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 353899.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 rank	MANE	Protein	UniProt
HSPB3	NM_006308.3 link	c.282G>A	p.Leu94Leu	synonymous_variant	Exon 1 of 1	ENST00000302005.3	NP_006299.1	Q12988Q6ICS9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HSPB3	ENST00000302005.3 link	c.282G>A	p.Leu94Leu	synonymous_variant	Exon 1 of 1	6	NM_006308.3	ENSP00000303394.1		Q12988

Frequencies

GnomAD3 genomes

AF:

0.537

AC:

81554

AN:

151744

Hom.:

22437

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.552

AC:

138678

AN:

251306

AF XY:

0.560

show subpopulations

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 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.:

AF XY:

0.581

AC XY:

422144

AN XY:

727168

show subpopulations

African (AFR)

AF:

0.445

AC:

14914

AN:

33478

American (AMR)

AF:

0.459

AC:

20536

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.602

AC:

15721

AN:

26134

East Asian (EAS)

AF:

0.345

AC:

13680

AN:

39700

South Asian (SAS)

AF:

0.554

AC:

47763

AN:

86254

European-Finnish (FIN)

AF:

0.616

AC:

32887

AN:

53418

Middle Eastern (MID)

AF:

0.679

AC:

3919

AN:

5768

European-Non Finnish (NFE)

AF:

0.597

AC:

663842

AN:

1111834

Other (OTH)

AF:

0.576

AC:

34808

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

24082

48163

72245

96326

120408

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

17972

35944

53916

71888

89860

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.537

AC:

81595

AN:

151862

Hom.:

22442

Cov.:

AF XY:

0.534

AC XY:

39611

AN XY:

74196

show subpopulations

African (AFR)

AF:

0.444

AC:

18374

AN:

41408

American (AMR)

AF:

0.475

AC:

7250

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.605

AC:

2097

AN:

3464

East Asian (EAS)

AF:

0.355

AC:

1822

AN:

5134

South Asian (SAS)

AF:

0.553

AC:

2654

AN:

4796

European-Finnish (FIN)

AF:

0.613

AC:

6471

AN:

10556

Middle Eastern (MID)

AF:

0.644

AC:

188

AN:

292

European-Non Finnish (NFE)

AF:

0.602

AC:

40921

AN:

67930

Other (OTH)

AF:

0.555

AC:

1166

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1879

3758

5636

7515

9394

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

718

1436

2154

2872

3590

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.568

Hom.:

53369

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:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Neuronopathy, distal hereditary motor, type 2C

Benign:4

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Nov 16, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:2

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.49

CADD

Benign

(source)

DANN

Benign

0.79

PhyloP100

0.53

PromoterAI

-0.076

Neutral

(source)

Mutation Taster

=98/2

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over