5-54456158-T-C

Variant names:

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.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

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.12

Publications

21 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=-0.94).

BP6

Variant 5-54456158-T-C is Benign according to our data. Variant chr5-54456158-T-C is described in ClinVar as Benign. ClinVar VariationId is 353903.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006308.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSPB3	NM_006308.3	MANE Select	c.369T>C	p.Gly123Gly	synonymous	Exon 1 of 1	NP_006299.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSPB3	ENST00000302005.3	TSL:6 MANE Select	c.369T>C	p.Gly123Gly	synonymous	Exon 1 of 1	ENSP00000303394.1

Frequencies

GnomAD3 genomes

AF:

0.631

AC:

95888

AN:

151888

Hom.:

30912

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.585

AC:

147027

AN:

251424

AF XY:

0.587

show subpopulations

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 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.:

AF XY:

0.606

AC XY:

440768

AN XY:

727102

show subpopulations

African (AFR)

AF:

0.744

AC:

24920

AN:

33476

American (AMR)

AF:

0.480

AC:

21479

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.593

AC:

15499

AN:

26134

East Asian (EAS)

AF:

0.347

AC:

13784

AN:

39700

South Asian (SAS)

AF:

0.571

AC:

49259

AN:

86246

European-Finnish (FIN)

AF:

0.628

AC:

33557

AN:

53418

Middle Eastern (MID)

AF:

0.696

AC:

4012

AN:

5766

European-Non Finnish (NFE)

AF:

0.619

AC:

687966

AN:

1111654

Other (OTH)

AF:

0.613

AC:

37015

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

21566

43132

64697

86263

107829

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18416

36832

55248

73664

92080

<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:

0.631

AC:

95978

AN:

152006

Hom.:

30948

Cov.:

AF XY:

0.626

AC XY:

46473

AN XY:

74294

show subpopulations

African (AFR)

AF:

0.734

AC:

30444

AN:

41462

American (AMR)

AF:

0.513

AC:

7831

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.590

AC:

2043

AN:

3462

East Asian (EAS)

AF:

0.358

AC:

1846

AN:

5154

South Asian (SAS)

AF:

0.565

AC:

2725

AN:

4820

European-Finnish (FIN)

AF:

0.627

AC:

6619

AN:

10564

Middle Eastern (MID)

AF:

0.663

AC:

195

AN:

294

European-Non Finnish (NFE)

AF:

0.622

AC:

42286

AN:

67962

Other (OTH)

AF:

0.634

AC:

1336

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1731

3462

5193

6924

8655

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

780

1560

2340

3120

3900

<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:

0.620

Hom.:

52323

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

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

Jan 13, 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.

Aug 10, 2021

Genome-Nilou Lab

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

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 v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.94

CADD

Benign

2.3

(source)

DANN

Benign

0.38

PhyloP100

-1.1

PromoterAI

-0.016

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over