chr7-76304115-C-T
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Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM1PM2PP5BP4
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
NM_001540.5 missense
Scores
6
13
Clinical Significance
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]
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ACMG classification
Classification made for transcript
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: {Uncertain_significance=1, Pathogenic=1, Likely_pathogenic=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 genomes
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32
GnomAD3 exomes AF: 0.00000407 AC: 1AN: 245998Hom.: 0 AF XY: 0.00000746 AC XY: 1AN XY: 134014
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GnomAD4 exome AF: 0.00000137 AC: 2AN: 1460970Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 726748
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GnomAD4 genome Cov.: 32
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32
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:2Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
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) - |
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 | - - |
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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
D;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Benign
T;T
M_CAP
Uncertain
D
MetaRNN
Benign
T;T
MetaSVM
Uncertain
T
MutationAssessor
Benign
L;.
MutationTaster
Benign
N;N
PrimateAI
Uncertain
T
PROVEAN
Benign
N;D
REVEL
Benign
Sift
Benign
T;D
Sift4G
Benign
T;D
Polyphen
B;.
Vest4
MutPred
Loss of disorder (P = 0.0356);.;
MVP
MPC
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at