rs375244209

chr7-76302870-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP5

The NM_001540.5(HSPB1):c.158G>A(p.Gly53Asp) variant causes a missense change. The variant allele was found at a frequency of 0.0000014 in 1,425,836 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G53G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: HSPB1 NM_001540.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: 4.89

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 Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a chain Heat shock protein beta-1 (size 204) in uniprot entity HSPB1_HUMAN there are 63 pathogenic changes around while only 11 benign (85%) in NM_001540.5
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-76302870-G-A is Pathogenic according to our data. Variant chr7-76302870-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 560408.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=1}. Variant chr7-76302870-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HSPB1	NM_001540.5	c.158G>A	p.Gly53Asp	missense_variant	1/3	ENST00000248553.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HSPB1	ENST00000248553.7	c.158G>A	p.Gly53Asp	missense_variant	1/3	1	NM_001540.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000109 AC: 2 AN: 183834 Hom.: 0 AF XY: 0.00000978 AC XY: 1 AN XY: 102264

Gnomad AFR exome AF: 0.000103

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000115

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000140 AC: 2 AN: 1425836 Hom.: 0 Cov.: 31 AF XY: 0.00000141 AC XY: 1 AN XY: 707318

Gnomad4 AFR exome AF: 0.0000304

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000392

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.: 33

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000227

ESP6500AA AF: 0.000256 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00000871 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 01, 2023	Reported in a heterozygous state in an individual with cerebellar ataxia (Echaniz-Laguna A et al., 2017); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32334137, 33943041, 32323160, 32639100, 28969372, 28144995) -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 19, 2021	- -

Neuronopathy, distal hereditary motor, type 2B Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Biochimie - Maladies Neurologiques Hereditaires, Hospices Civils de Lyon

Feb 02, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
Cadd	Pathogenic	29
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.75	D
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.85	D
M_CAP	Pathogenic	0.74	D
MetaRNN	Uncertain	0.70	D
MetaSVM	Uncertain	0.71	D
MutationAssessor	Benign	1.8	L
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-2.8	D
REVEL	Pathogenic	0.72
Sift	Benign	0.050	D
Sift4G	Benign	0.15	T
Polyphen		1.0	D
Vest4		0.52
MVP		0.98
MPC		1.7
ClinPred		0.99	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.77
gMVP		0.89

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: rs375244209; hg19: chr7-75932187;