rs28939680

Positions:

• chr7-76303841-C-A
• chr7-76303841-C-G
• chr7-76303841-C-T

Variant summary

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

The ENST00000248553.7(HSPB1):​c.404C>A​(p.Ser135Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,459,296 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S135C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: HSPB1 ENST00000248553.7 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2 U:1
• Conservation: PhyloP100: 5.22

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, 11 uncertain in ENST00000248553.7
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-76303841-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 637060.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.956
• PP5: Variant 7-76303841-C-A is Pathogenic according to our data. Variant chr7-76303841-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 533813.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-76303841-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HSPB1	NM_001540.5	c.404C>A	p.Ser135Tyr	missense_variant	2/3	ENST00000248553.7	NP_001531.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HSPB1	ENST00000248553.7	c.404C>A	p.Ser135Tyr	missense_variant	2/3	1	NM_001540.5	ENSP00000248553	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459296 Hom.: 0 Cov.: 34 AF XY: 0.00000276 AC XY: 2 AN XY: 725916

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: 0.0000381

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 12, 2019

This variant has been reported in individuals affected with distal hereditary motor neuropathy and Charcot-Marie-Tooth disease (PMID: 27816334, 23963299, Invitae) and has been reported to segregate with Charcot-Marie-Tooth disease in a single family (PMID: 23963299). This variant is not present in population databases (ExAC no frequency). This sequence change replaces serine with tyrosine at codon 135 of the HSPB1 protein (p.Ser135Tyr). The serine residue is highly conserved and there is a large physicochemical difference between serine and tyrosine. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). For these reasons, this variant has been classified as Pathogenic. A different missense substitution at this codon (p.Ser135Phe) has been determined to be pathogenic (PMID: 15122254, 18832141, 17881652). This suggests that the serine residue is critical for HSPB1 protein function and that other missense substitutions at this position may also be pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Oct 23, 2020

- -

Charcot-Marie-Tooth disease Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

Inherited Neuropathy Consortium

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.94	D
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.77	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Uncertain	2.3	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-5.1	D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.99	D
Vest4		0.95
MutPred		0.64		Loss of disorder (P = 0.0352);
MVP		0.99
MPC		1.7
ClinPred		1.0	D
GERP RS		4.4
Varity_R		0.97
gMVP		0.80

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: rs28939680; hg19: chr7-75933158;