NM_001540.5:c.180delC

Variant names:

• chr7-76302886-GC-G
• rs1064796370
• NM_001540.5:c.180delC

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_001540.5(HSPB1):​c.180delC​(p.Ala61ProfsTer49) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000711 in 1,407,162 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. P60P) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: HSPB1 NM_001540.5 frameshift
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.897
• Publications: 0 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 2F

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Illumina, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet
• neuronopathy, distal hereditary motor, type 2B

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• distal hereditary motor neuropathy type 2

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000296557 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSPB1	NM_001540.5	MANE Select	c.180delC	p.Ala61ProfsTer49	frameshift	Exon 1 of 3	NP_001531.1	P04792

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSPB1	ENST00000248553.7	TSL:1 MANE Select	c.180delC	p.Ala61ProfsTer49	frameshift	Exon 1 of 3	ENSP00000248553.6	P04792
	HSPB1	ENST00000447574.1	TSL:1	n.205delC		non_coding_transcript_exon	Exon 1 of 2
	HSPB1	ENST00000676231.2		c.180delC	p.Ala61ProfsTer49	frameshift	Exon 1 of 4	ENSP00000502249.1	A0A6Q8PGK1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.11e-7 AC: 1 AN: 1407162 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 696616

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32428

American (AMR) AF: 0.00 AC: 0 AN: 38406

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25284

East Asian (EAS) AF: 0.00 AC: 0 AN: 37262

South Asian (SAS) AF: 0.00 AC: 0 AN: 81774

European-Finnish (FIN) AF: 0.0000261 AC: 1 AN: 38292

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5012

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1090218

Other (OTH) AF: 0.00 AC: 0 AN: 58486

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Charcot-Marie-Tooth disease axonal type 2F (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.90

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

Other links and lift over

dbSNP: rs1064796370; hg19: chr7-75932203;