rs1422978230

Positions:

• chr7-76304094-C-G
• chr7-76304094-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 4P and 5B. PM1 PM5 BP4 BS2

The NM_001540.5(HSPB1):​c.539C>G​(p.Thr180Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000821 in 1,461,474 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T180I) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: HSPB1 NM_001540.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter 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]

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 9 uncertain in NM_001540.5
• PM5: Other missense variant is known to change same aminoacid residue: 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.27446377).
• BS2: High AC in GnomAdExome4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HSPB1	NM_001540.5	c.539C>G	p.Thr180Ser	missense_variant	3/3	ENST00000248553.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HSPB1	ENST00000248553.7	c.539C>G	p.Thr180Ser	missense_variant	3/3	1	NM_001540.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461474 Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3 AN XY: 727000

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: 0.0000108

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 18, 2018

This variant disrupts the p.Thr180 amino acid residue in HSPB1. Another variant that disrupts this residue has been observed in individuals with HSPB1-related conditions (PMID: 27862672, 20870250, 22176143, 28144995), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed in an individual affected with clinical features of Charcot-Marie-Tooth disease type 2 (Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change replaces threonine with serine at codon 180 of the HSPB1 protein (p.Thr180Ser). The threonine residue is moderately conserved and there is a small physicochemical difference between threonine and serine. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Uncertain	0.096	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	21
DANN	Benign	0.94
DEOGEN2	Uncertain	0.61	D;T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.14
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.67	T;T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.27	T;T
MetaSVM	Uncertain	-0.10	T
MutationAssessor	Benign	0.29	N;.
MutationTaster	Benign	0.82	D;N
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.6	N;D
REVEL	Uncertain	0.33
Sift	Benign	0.37	T;D
Sift4G	Benign	0.68	T;D
Polyphen		0.020	B;.
Vest4		0.13
MutPred		0.35		Gain of glycosylation at T180 (P = 0.0893);.;
MVP		0.98
MPC		0.71
ClinPred		0.52	D
GERP RS		4.7
Varity_R		0.37
gMVP		0.62

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;