dbSNP rs139382018: HSPB3:p.Arg7Ser (chr5-54455810-G-T) – ACMG Classification: Benign (-16 pts)

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_006308.3(HSPB3):c.21G>T(p.Arg7Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000489 in 1,613,976 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00055 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00048 ( 4 hom. )

Consequence

HSPB3
NM_006308.3 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts P:1B:2

Conservation

PhyloP100: 0.806

Publications

17 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: Labcorp Genetics (formerly Invitae), Ambry Genetics

HSPB3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.037616163).

BP6

Variant 5-54455810-G-T is Benign according to our data. Variant chr5-54455810-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 5429.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 84 AD gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSPB3	NM_006308.3	MANE Select	c.21G>T	p.Arg7Ser	missense	Exon 1 of 1	NP_006299.1	Q6ICS9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSPB3	ENST00000302005.3	TSL:6 MANE Select	c.21G>T	p.Arg7Ser	missense	Exon 1 of 1	ENSP00000303394.1	Q12988

Frequencies

GnomAD3 genomes

AF:

0.000552

AC:

AN:

152102

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00132

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00101

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.000518

AC:

130

AN:

251204

AF XY:

0.000471

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00176

Gnomad NFE exome

AF:

0.000758

Gnomad OTH exome

AF:

0.000816

GnomAD4 exome

AF:

0.000482

AC:

705

AN:

1461874

Hom.:

Cov.:

AF XY:

0.000479

AC XY:

348

AN XY:

727242

show subpopulations

African (AFR)

AF:

0.0000597

AC:

AN:

33480

American (AMR)

AF:

0.0000224

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00161

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000540

AC:

601

AN:

1111992

Other (OTH)

AF:

0.000232

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

127

170

212

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.000552

AC:

AN:

152102

Hom.:

Cov.:

AF XY:

0.000633

AC XY:

AN XY:

74274

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41436

American (AMR)

AF:

0.00

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00

AC:

AN:

4808

European-Finnish (FIN)

AF:

0.00132

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00101

AC:

AN:

68014

Other (OTH)

AF:

0.000479

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000640

Hom.:

Bravo

AF:

0.000340

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000502

AC:

EpiCase

AF:

0.000545

EpiControl

AF:

0.000356

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Neuronopathy, distal hereditary motor, type 2C (2)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.61

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Uncertain

0.060

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.046

Eigen

Benign

0.079

Eigen_PC

Benign

0.12

FATHMM_MKL

Benign

0.72

LIST_S2

Benign

0.71

M_CAP

Uncertain

0.091

MetaRNN

Benign

0.038

MetaSVM

Uncertain

0.19

MutationAssessor

Benign

1.9

PhyloP100

0.81

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-1.0

REVEL

Uncertain

0.61

Sift

Benign

0.19

Sift4G

Benign

0.21

Polyphen

0.83

Vest4

0.29

MutPred

0.89

Loss of MoRF binding (P = 3e-04)

MVP

0.80

MPC

0.17

ClinPred

0.033

GERP RS

4.3

PromoterAI

0.065

Neutral

(source)

Varity_R

0.12

gMVP

0.69

Mutation Taster

=71/29

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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

Computational scores

Splicing

Publications

Other links and lift over