Genetic Variant HSPB1:p.Gly84Arg (chr7-76302962-G-C) – ACMG Classification: Pathogenic (24 pts)

Variant summary

Our verdict is Pathogenic. The variant received 24 ACMG points: 28P and 4B. PS1_Very_StrongPS3PM1PM5PP3_StrongPP5_Very_StrongBS2

The NM_001540.5(HSPB1):c.250G>C(p.Gly84Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000214 in 1,544,310 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000260941: Experimental studies have shown that this missense change affects HSPB1 function (PMID:18344398, 23948568)." and additional evidence is available in ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G84W) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

HSPB1
NM_001540.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10U:1

Conservation

PhyloP100: 5.12

Publications

24 publications found

Variant links:

Genes affected

HSPB1 (HGNC:5246): (heat shock protein family B (small) member 1) This gene encodes a member of the small heat shock protein (HSP20) family of proteins. In response to environmental stress, the encoded protein translocates from the cytoplasm to the nucleus and functions as a molecular chaperone that promotes the correct folding of other proteins. This protein plays an important role in the differentiation of a wide variety of cell types. Expression of this gene is correlated with poor clinical outcome in multiple human cancers, and the encoded protein may promote cancer cell proliferation and metastasis, while protecting cancer cells from apoptosis. Mutations in this gene have been identified in human patients with Charcot-Marie-Tooth disease and distal hereditary motor neuropathy. [provided by RefSeq, Aug 2017]

HSPB1 Gene-Disease associations (from GenCC):

Charcot-Marie-Tooth disease axonal type 2F
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Illumina, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet
neuronopathy, distal hereditary motor, type 2B
Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
distal hereditary motor neuropathy type 2
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

HSPB1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 24 ACMG points.

PS1

Transcript NM_001540.5 (HSPB1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.

PS3

PS3 evidence extracted from ClinVar submissions: SCV000260941: Experimental studies have shown that this missense change affects HSPB1 function (PMID: 18344398, 23948568).; SCV005324948: Published functional studies demonstrate a damaging effect on protein stability and ability to form large heterooligomers (PMID: 23948568), as well as enhanced cytoplasmic aggregation of the mutant protein (PMID: 18344398); SCV002744256: This alteration has been reported in multiple patients with neuropathy in both heterozygous and homozygous states and has been functionally studied and shown to result in a defective protein. (Houlden H et al. Neurology, 2008 Nov;71:1660-8; James PA et al. J. Neurol. Neurosurg. Psychiatry, 2008 Apr;79:461-3; Fischer C et al. J. Neurol., 2012 Mar;259:515-23; Nefedova VV et al. Arch. Biochem. Biophys., 2013 Oct;538:16-24; Manganelli F et al. J. Peripher. Nerv. Syst., 2014 Dec;19:292-8; Ho CC et al. Int J Mol Sci, 2017 Apr;18:(4). pii: E770).; SCV004812353: Expression of the variant in heterologous systems showed protein aggregate formation, altered protein oligomerisation, and decreased charperone-like acitivty indicating that this variant impacts protein function (PMID: 18344398, 23948568).

PM1

In a domain sHSP (size 108) in uniprot entity HSPB1_HUMAN there are 22 pathogenic changes around while only 2 benign (92%) in NM_001540.5

PM5

Other missense variant is known to change same aminoacid residue: Variant chr7-76302962-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 948718.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.983

PP5

Variant 7-76302962-G-C is Pathogenic according to our data. Variant chr7-76302962-G-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 220419.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAdExome4 at 32 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001540.5. 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
	HSPB1	NM_001540.5	MANE Select	c.250G>C	p.Gly84Arg	missense	Exon 1 of 3	NP_001531.1	P04792

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HSPB1	ENST00000248553.7	TSL:1 MANE Select	c.250G>C	p.Gly84Arg	missense	Exon 1 of 3	ENSP00000248553.6	P04792
HSPB1	ENST00000447574.1	TSL:1	n.275G>C		non_coding_transcript_exon	Exon 1 of 2
HSPB1	ENST00000676231.2		c.250G>C	p.Gly84Arg	missense	Exon 1 of 4	ENSP00000502249.1	A0A6Q8PGK1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000678

AC:

AN:

147494

AF XY:

0.0000124

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000166

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000230

AC:

AN:

1392122

Hom.:

Cov.:

AF XY:

0.0000204

AC XY:

AN XY:

687784

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32090

American (AMR)

AF:

0.00

AC:

AN:

36376

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25212

East Asian (EAS)

AF:

0.00

AC:

AN:

36426

South Asian (SAS)

AF:

0.00

AC:

AN:

80298

European-Finnish (FIN)

AF:

0.00

AC:

AN:

35658

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5548

European-Non Finnish (NFE)

AF:

0.0000286

AC:

AN:

1082396

Other (OTH)

AF:

0.0000172

AC:

AN:

58118

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152188

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74354

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41434

American (AMR)

AF:

0.00

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68040

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Charcot-Marie-Tooth disease (2)

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

Charcot-Marie-Tooth disease axonal type 2F (1)

Distal hereditary motor neuropathy type 2 (1)

Distal spinal muscular atrophy (1)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Pathogenic

0.43

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.86

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

M_CAP

Pathogenic

0.96

MetaRNN

Pathogenic

0.98

MetaSVM

Pathogenic

0.92

MutationAssessor

Pathogenic

2.9

PhyloP100

5.1

PrimateAI

Pathogenic

0.92

PROVEAN

Pathogenic

-5.4

REVEL

Pathogenic

0.91

Sift

Pathogenic

0.0

Sift4G

Benign

0.063

Polyphen

1.0

Vest4

0.97

MutPred

0.81

Gain of solvent accessibility (P = 0.0128)

MVP

0.99

MPC

1.7

ClinPred

0.99

GERP RS

4.9

PromoterAI

0.050

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.91

gMVP

0.74

Mutation Taster

=2/98

disease causing (ClinVar)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over