rs863225022

Positions:

• chr7-76303844-G-A
• chr7-76303844-G-C
• chr7-76303844-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_001540.5(HSPB1):​c.407G>A​(p.Arg136Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,459,318 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R136L) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: HSPB1 NM_001540.5 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 6.93

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_001540.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-76303844-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 217230.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant 7-76303844-G-A is Pathogenic according to our data. Variant chr7-76303844-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 810107.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HSPB1	NM_001540.5	c.407G>A	p.Arg136Gln	missense_variant	2/3	ENST00000248553.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HSPB1	ENST00000248553.7	c.407G>A	p.Arg136Gln	missense_variant	2/3	1	NM_001540.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459318 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 725914

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Charcot-Marie-Tooth disease axonal type 2F Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 26, 2022

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Arg136 amino acid residue in HSPB1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21611841, 22176143, 25547330, 26989944). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt HSPB1 protein function. ClinVar contains an entry for this variant (Variation ID: 810107). This variant has not been reported in the literature in individuals affected with HSPB1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 136 of the HSPB1 protein (p.Arg136Gln). -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Apr 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	35
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.95	D
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.75	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	2.9	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-3.7	D
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.011	D
Polyphen		1.0	D
Vest4		0.81
MutPred		0.88		Gain of ubiquitination at K141 (P = 0.0476);
MVP		0.99
MPC		1.6
ClinPred		1.0	D
GERP RS		4.4
Varity_R		0.97
gMVP		0.84

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

LitVar

Other links and lift over

dbSNP: rs863225022; hg19: chr7-75933161;