NM_001540.5:c.-19C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001540.5(HSPB1):c.-19C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00224 in 1,598,998 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0014 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0023 ( 5 hom. )

Consequence

HSPB1
NM_001540.5 5_prime_UTR

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.294

Publications

1 publications found

Variant links:

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 Gene-Disease associations (from GenCC):

Charcot-Marie-Tooth disease axonal type 2F
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Illumina, Labcorp Genetics (formerly Invitae), Orphanet
neuronopathy, distal hereditary motor, type 2B
Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
distal hereditary motor neuropathy type 2
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

HSPB1 links:

ENSG00000296557 (HGNC:):

ENSG00000296557 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BP6

Variant 7-76302694-C-T is Benign according to our data. Variant chr7-76302694-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 258165.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00142 (217/152356) while in subpopulation NFE AF = 0.00276 (188/68030). AF 95% confidence interval is 0.00244. There are 0 homozygotes in GnomAd4. There are 101 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 217 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001540.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSPB1	NM_001540.5	MANE Select	c.-19C>T		5_prime_UTR	Exon 1 of 3	NP_001531.1	P04792

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
HSPB1	ENST00000248553.7	TSL:1 MANE Select	c.-19C>T	5_prime_UTR	Exon 1 of 3	ENSP00000248553.6	P04792
HSPB1	ENST00000447574.1	TSL:1	n.7C>T	non_coding_transcript_exon	Exon 1 of 2
HSPB1	ENST00000676231.2		c.-19C>T	5_prime_UTR	Exon 1 of 4	ENSP00000502249.1	A0A6Q8PGK1

Frequencies

GnomAD3 genomes

AF:

0.00143

AC:

217

AN:

152238

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000386

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000413

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00276

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.00140

AC:

327

AN:

234382

AF XY:

0.00147

show subpopulations

Gnomad AFR exome

AF:

0.000211

Gnomad AMR exome

AF:

0.000524

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000230

Gnomad NFE exome

AF:

0.00254

Gnomad OTH exome

AF:

0.00186

GnomAD4 exome

AF:

0.00233

AC:

3364

AN:

1446642

Hom.:

Cov.:

AF XY:

0.00229

AC XY:

1648

AN XY:

720218

show subpopulations

African (AFR)

AF:

0.000269

AC:

AN:

33414

American (AMR)

AF:

0.000492

AC:

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26116

East Asian (EAS)

AF:

0.00

AC:

AN:

39682

South Asian (SAS)

AF:

0.000615

AC:

AN:

86166

European-Finnish (FIN)

AF:

0.000422

AC:

AN:

40312

Middle Eastern (MID)

AF:

0.000465

AC:

AN:

4298

European-Non Finnish (NFE)

AF:

0.00283

AC:

3145

AN:

1111802

Other (OTH)

AF:

0.00191

AC:

115

AN:

60142

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

203

406

608

811

1014

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

118

236

354

472

590

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00142

AC:

217

AN:

152356

Hom.:

Cov.:

AF XY:

0.00136

AC XY:

101

AN XY:

74502

show subpopulations

African (AFR)

AF:

0.000385

AC:

AN:

41600

American (AMR)

AF:

0.000588

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.000414

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00276

AC:

188

AN:

68030

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00121

Hom.:

Bravo

AF:

0.00146

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (3)

Charcot-Marie-Tooth disease (1)

Charcot-Marie-Tooth disease axonal type 2F (1)

Neuronopathy, distal hereditary motor, type 2B (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

3.4

(source)

DANN

Benign

0.74

PhyloP100

-0.29

PromoterAI

-0.021

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Mutation Taster

=300/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over