7-76304094-C-T

Position:

• chr7-76304094-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PP5_Very_Strong

The NM_001540.5(HSPB1):​c.539C>T​(p.Thr180Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,474 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: HSPB1 NM_001540.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2 U:1
• Conservation: PhyloP100: 2.00

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM1: In a region_of_interest Interaction with TGFB1I1 (size 135) in uniprot entity HSPB1_HUMAN there are 28 pathogenic changes around while only 1 benign (97%) in NM_001540.5
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-76304094-C-T is Pathogenic according to our data. Variant chr7-76304094-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 447531.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-76304094-C-T is described in Lovd as [Pathogenic]. Variant chr7-76304094-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HSPB1	NM_001540.5	c.539C>T	p.Thr180Ile	missense_variant	3/3	ENST00000248553.7	NP_001531.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HSPB1	ENST00000248553.7	c.539C>T	p.Thr180Ile	missense_variant	3/3	1	NM_001540.5	ENSP00000248553.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461474 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727000

Gnomad4 AFR exome AF: 0.0000299

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: 0.00

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

Apr 15, 2019

This variant has been observed to be de novo in individuals affected with Charcot-Marie-Tooth disease, type 2 or distal hereditary motor neuropathy (PMID: 20870250, 28144995). This variant has also been observed in additional individuals affected with Charcot-Marie-Tooth disease, type 2 or distal hereditary motor neuropathy (PMID: 22176143, 26989944, 27862672). ClinVar contains an entry for this variant (Variation ID: 447531). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change results in an HSPB1 protein with a small increase of thermal stability, but without changes of chaperone-like activity (PMID: 25220807). This variant is not present in population databases (ExAC no frequency). This sequence change replaces threonine with isoleucine at codon 180 of the HSPB1 protein (p.Thr180Ile). The threonine residue is moderately conserved and there is a moderate physicochemical difference between threonine and isoleucine. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Athena Diagnostics

Feb 23, 2017

- -

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	Benign	0.25
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Benign	22
DANN	Benign	0.96
DEOGEN2	Pathogenic	0.80	D;T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.086
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.81	T;T
M_CAP	Uncertain	0.16	D
MetaRNN	Uncertain	0.63	D;D
MetaSVM	Uncertain	0.38	D
MutationAssessor	Benign	1.5	L;.
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-2.3	N;D
REVEL	Uncertain	0.61
Sift	Benign	0.19	T;D
Sift4G	Benign	0.19	T;D
Polyphen		0.056	B;.
Vest4		0.61
MutPred		0.39		Loss of glycosylation at T180 (P = 0.0305);.;
MVP		0.99
MPC		1.5
ClinPred		0.90	D
GERP RS		4.7
Varity_R		0.51
gMVP		0.69

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: rs1422978230; hg19: chr7-75933411;