rs34771861

Positions:

• chr7-76304128-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001540.5(HSPB1):​c.573T>C​(p.Leu191=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0003 in 1,612,508 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0016 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00017 (1 hom.)
• Consequence: HSPB1 NM_001540.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.965

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 7-76304128-T-C is Benign according to our data. Variant chr7-76304128-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 385089.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.965 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00157 (239/152092) while in subpopulation AFR AF= 0.00547 (227/41518). AF 95% confidence interval is 0.00488. There are 1 homozygotes in gnomad4. There are 95 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 239 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HSPB1	NM_001540.5	c.573T>C	p.Leu191=	synonymous_variant	3/3	ENST00000248553.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HSPB1	ENST00000248553.7	c.573T>C	p.Leu191=	synonymous_variant	3/3	1	NM_001540.5	P1

Frequencies

GnomAD3 genomes AF: 0.00157 AC: 238 AN: 151974 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00546

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000459

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000409 AC: 100 AN: 244774 Hom.: 0 AF XY: 0.000300 AC XY: 40 AN XY: 133484

Gnomad AFR exome AF: 0.00537

Gnomad AMR exome AF: 0.000408

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000550

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000182

Gnomad OTH exome AF: 0.000337

GnomAD4 exome AF: 0.000167 AC: 244 AN: 1460416 Hom.: 1 Cov.: 33 AF XY: 0.000151 AC XY: 110 AN XY: 726462

Gnomad4 AFR exome AF: 0.00562

Gnomad4 AMR exome AF: 0.000426

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000349

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.000448

GnomAD4 genome AF: 0.00157 AC: 239 AN: 152092 Hom.: 1 Cov.: 32 AF XY: 0.00128 AC XY: 95 AN XY: 74338

Gnomad4 AFR AF: 0.00547

Gnomad4 AMR AF: 0.000459

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000642 Hom.: 0

Bravo AF: 0.00164

Asia WGS AF: 0.000578 AC: 2 AN: 3476

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 22, 2020	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Nov 12, 2020

- -

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

Jul 11, 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. -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 24, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	3.9
DANN	Benign	0.73
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs34771861; hg19: chr7-75933445;