Genetic Variant HSPB8:p.Pro107Thr (chr12-119179631-C-A) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_014365.3(HSPB8):c.319C>A(p.Pro107Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000000692 in 1,444,410 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P107S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

HSPB8
NM_014365.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.48

Publications

0 publications found

Variant links:

Genes affected

HSPB8 (HGNC:30171): (heat shock protein family B (small) member 8) The protein encoded by this gene belongs to the superfamily of small heat-shock proteins containing a conservative alpha-crystallin domain at the C-terminal part of the molecule. The expression of this gene in induced by estrogen in estrogen receptor-positive breast cancer cells, and this protein also functions as a chaperone in association with Bag3, a stimulator of macroautophagy. Thus, this gene appears to be involved in regulation of cell proliferation, apoptosis, and carcinogenesis, and mutations in this gene have been associated with different neuromuscular diseases, including Charcot-Marie-Tooth disease. [provided by RefSeq, Jul 2008]

HSPB8 Gene-Disease associations (from GenCC):

neuronopathy, distal hereditary motor, autosomal dominant
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
Charcot-Marie-Tooth disease axonal type 2L
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
neuronopathy, distal hereditary motor, type 2A
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
autosomal dominant distal axonal motor neuropathy-myofibrillar myopathy syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
distal hereditary motor neuropathy type 2
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

HSPB8 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.94

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSPB8	NM_014365.3 link	c.319C>A	p.Pro107Thr	missense_variant	Exon 1 of 3	ENST00000281938.7	NP_055180.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
HSPB8	ENST00000281938.7 link	c.319C>A	p.Pro107Thr	missense_variant	Exon 1 of 3	1	NM_014365.3	ENSP00000281938.3
HSPB8	ENST00000541798.1 link	c.40C>A	p.Pro14Thr	missense_variant	Exon 1 of 4	3		ENSP00000441541.1
HSPB8	ENST00000674542.1 link	c.319C>A	p.Pro107Thr	missense_variant	Exon 1 of 2			ENSP00000502352.1
HSPB8	ENST00000676244.1 link	n.73+5633C>A		intron_variant	Intron 1 of 2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.92e-7

AC:

AN:

1444410

Hom.:

Cov.:

AF XY:

0.00000140

AC XY:

AN XY:

716768

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

32816

American (AMR)

AF:

0.00

AC:

AN:

42082

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24898

East Asian (EAS)

AF:

0.00

AC:

AN:

39458

South Asian (SAS)

AF:

0.0000120

AC:

AN:

83524

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52824

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5656

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1103574

Other (OTH)

AF:

0.00

AC:

AN:

59578

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.89

BayesDel_addAF

Pathogenic

0.45

BayesDel_noAF

Pathogenic

0.40

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.93

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Benign

0.59

LIST_S2

Uncertain

0.93

M_CAP

Uncertain

0.19

MetaRNN

Pathogenic

0.94

MetaSVM

Uncertain

0.20

MutationAssessor

Pathogenic

3.4

PhyloP100

5.5

PrimateAI

Pathogenic

0.86

PROVEAN

Pathogenic

-7.0

REVEL

Pathogenic

0.84

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0040

Polyphen

1.0

Vest4

0.80

MutPred

0.81

Gain of catalytic residue at F105 (P = 0.0044);

MVP

0.96

MPC

0.81

ClinPred

0.99

GERP RS

4.2

PromoterAI

-0.028

Neutral

(source)

Varity_R

0.97

gMVP

0.80

Mutation Taster

=21/79

disease causing

(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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over