rs762032846
Variant names:
Variant summary
Our verdict is Benign. The variant received -9 ACMG points: 2P and 11B. PM2BP4_ModerateBP6_Very_StrongBP7
The NM_001540.5(HSPB1):c.99C>T(p.Phe33Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,455,242 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 Likely benign (★★).
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
HSPB1
NM_001540.5 synonymous
NM_001540.5 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 1.03
Publications
1 publications found
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]
HSPB1 Gene-Disease associations (from GenCC):
- Charcot-Marie-Tooth disease axonal type 2FInheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, Illumina, Labcorp Genetics (formerly Invitae)
- neuronopathy, distal hereditary motor, type 2BInheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
- distal hereditary motor neuropathy type 2Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Genome browser will be placed here
ACMG classification
Classification was made for transcript
Our verdict: Benign. The variant received -9 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.22).
BP6
Variant 7-76302811-C-T is Benign according to our data. Variant chr7-76302811-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 220380.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
Synonymous conserved (PhyloP=1.03 with no splicing effect.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_001540.5. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| HSPB1 | NM_001540.5 | MANE Select | c.99C>T | p.Phe33Phe | synonymous | Exon 1 of 3 | NP_001531.1 |
Ensembl Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| HSPB1 | ENST00000248553.7 | TSL:1 MANE Select | c.99C>T | p.Phe33Phe | synonymous | Exon 1 of 3 | ENSP00000248553.6 | ||
| HSPB1 | ENST00000447574.1 | TSL:1 | n.124C>T | non_coding_transcript_exon | Exon 1 of 2 | ||||
| HSPB1 | ENST00000676231.2 | c.99C>T | p.Phe33Phe | synonymous | Exon 1 of 4 | ENSP00000502249.1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
33
GnomAD2 exomes AF: 0.00000860 AC: 2AN: 232452 AF XY: 0.00 show subpopulations
GnomAD2 exomes
AF:
AC:
2
AN:
232452
AF XY:
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1455242Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 723968 show subpopulations ⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
GnomAD4 exome
AF:
AC:
2
AN:
1455242
Hom.:
Cov.:
31
AF XY:
AC XY:
0
AN XY:
723968
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
AC:
0
AN:
33420
American (AMR)
AF:
AC:
2
AN:
44452
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
26014
East Asian (EAS)
AF:
AC:
0
AN:
39618
South Asian (SAS)
AF:
AC:
0
AN:
85878
European-Finnish (FIN)
AF:
AC:
0
AN:
49216
Middle Eastern (MID)
AF:
AC:
0
AN:
5528
European-Non Finnish (NFE)
AF:
AC:
0
AN:
1111042
Other (OTH)
AF:
AC:
0
AN:
60074
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00233887), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.350
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
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0.60
0.80
0.95
Allele balance
Age Distribution
Exome Het
Variant carriers
0
2
4
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<30
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Age
GnomAD4 genome
GnomAD4 genome
Cov.:
33
Alfa
AF:
Hom.:
Bravo
AF:
ClinVar
ClinVar submissions as Germline
Significance:Likely benign
Revision:criteria provided, multiple submitters, no conflicts
Pathogenic
VUS
Benign
Condition
-
-
1
Charcot-Marie-Tooth disease axonal type 2F (1)
-
-
1
Inborn genetic diseases (1)
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
DANN
Benign
PhyloP100
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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