7-76304115-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM1 PM2 PP5 BP4

The NM_001540.5(HSPB1):c.560C>T(p.Ser187Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,970 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: HSPB1 NM_001540.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 2.13

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 Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 11 uncertain in NM_001540.5
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-76304115-C-T is Pathogenic according to our data. Variant chr7-76304115-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 560409.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Pathogenic=1, Uncertain_significance=1}. Variant chr7-76304115-C-T is described in Lovd as [Likely_pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.24470836).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HSPB1	NM_001540.5	c.560C>T	p.Ser187Leu	missense_variant	3/3	ENST00000248553.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HSPB1	ENST00000248553.7	c.560C>T	p.Ser187Leu	missense_variant	3/3	1	NM_001540.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000407 AC: 1 AN: 245998 Hom.: 0 AF XY: 0.00000746 AC XY: 1 AN XY: 134014

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000906

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460970 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 726748

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Neuronopathy, distal hereditary motor, type 2B Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Biochimie - Maladies Neurologiques Hereditaires, Hospices Civils de Lyon

Feb 02, 2017

- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Athena Diagnostics

Mar 31, 2023

The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with Charcot-Marie-Tooth disease and appears to occur de novo in one individual with distal hereditary motor neuropathy. Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 28144995) -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jun 25, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies have shown that this missense change affects HSPB1 function (PMID: 28144995). 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: 560409). This missense change has been observed in individual(s) with distal hereditary motor neuropathy (PMID: 28144995). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 187 of the HSPB1 protein (p.Ser187Leu). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Uncertain	0.050	T
BayesDel_noAF	Benign	-0.17
Cadd	Uncertain	23
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.54	D;T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.42	N
LIST_S2	Benign	0.76	T;T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.24	T;T
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Benign	1.9	L;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-2.2	N;D
REVEL	Benign	0.26
Sift	Benign	0.10	T;D
Sift4G	Benign	0.23	T;D
Polyphen		0.30	B;.
Vest4		0.22
MutPred		0.39		Loss of disorder (P = 0.0356);.;
MVP		0.96
MPC		0.50
ClinPred		0.19	T
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.27
gMVP		0.51

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: rs774585320; hg19: chr7-75933432;