rs61751217

Positions:

• chr7-76302890-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001540.5(HSPB1):​c.178C>T​(p.Pro60Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00228 in 1,560,540 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P60R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0024 (5 hom.)
• Consequence: HSPB1 NM_001540.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -0.134

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 Benign. Variant got -18 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
• BP4: Computational evidence support a benign effect (MetaRNN=0.005441934).
• BP6: Variant 7-76302890-C-T is Benign according to our data. Variant chr7-76302890-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 239028.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-76302890-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00145 (221/152336) while in subpopulation NFE AF= 0.00278 (189/68024). AF 95% confidence interval is 0.00245. There are 0 homozygotes in gnomad4. There are 102 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 221 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HSPB1	NM_001540.5	c.178C>T	p.Pro60Ser	missense_variant	1/3	ENST00000248553.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HSPB1	ENST00000248553.7	c.178C>T	p.Pro60Ser	missense_variant	1/3	1	NM_001540.5	P1

Frequencies

GnomAD3 genomes AF: 0.00145 AC: 221 AN: 152218 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000458

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00278

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00154 AC: 252 AN: 164092 Hom.: 1 AF XY: 0.00158 AC XY: 144 AN XY: 90992

Gnomad AFR exome AF: 0.000357

Gnomad AMR exome AF: 0.000593

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000561

Gnomad FIN exome AF: 0.000118

Gnomad NFE exome AF: 0.00301

Gnomad OTH exome AF: 0.00197

GnomAD4 exome AF: 0.00237 AC: 3335 AN: 1408204 Hom.: 5 Cov.: 31 AF XY: 0.00234 AC XY: 1628 AN XY: 697212

Gnomad4 AFR exome AF: 0.000308

Gnomad4 AMR exome AF: 0.000519

Gnomad4 ASJ exome AF: 0.0000395

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000623

Gnomad4 FIN exome AF: 0.000444

Gnomad4 NFE exome AF: 0.00286

Gnomad4 OTH exome AF: 0.00193

GnomAD4 genome AF: 0.00145 AC: 221 AN: 152336 Hom.: 0 Cov.: 33 AF XY: 0.00137 AC XY: 102 AN XY: 74482

Gnomad4 AFR AF: 0.000457

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.00278

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00171 Hom.: 0

Bravo AF: 0.00148

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00157 AC: 11

ExAC AF: 0.00103 AC: 114

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 07, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	HSPB1: BS1 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 01, 2023	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 18, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 16, 2016	- -

Charcot-Marie-Tooth disease axonal type 2F Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	May 22, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Charcot-Marie-Tooth disease Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

-

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 20, 2019

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

May 22, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	12
DANN	Benign	0.91
DEOGEN2	Benign	0.31	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.49	N
LIST_S2	Benign	0.64	T
MetaRNN	Benign	0.0054	T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	-0.30	N
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.88	N
REVEL	Benign	0.23
Sift	Benign	0.39	T
Sift4G	Benign	0.48	T
Polyphen		0.0	B
Vest4		0.058
MVP		0.63
MPC		0.56
ClinPred		0.0037	T
GERP RS		-3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.6
Varity_R		0.025
gMVP		0.50

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: rs61751217; hg19: chr7-75932207;