7-76304184-C-T

Variant names:

• chr7-76304184-C-T
• rs1058872
• NM_001540.5:c.*11C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001540.5(HSPB1):​c.*11C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.013 in 1,604,494 control chromosomes in the GnomAD database, including 309 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (100 hom., cov: 32)
  • Exomes 𝑓: 0.012 (209 hom.)
• Consequence: HSPB1 NM_001540.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.13
• Publications: 5 publications found

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: Orphanet, ClinGen, Illumina, Labcorp Genetics (formerly Invitae)
• 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 7-76304184-C-T is Benign according to our data. Variant chr7-76304184-C-T is described in ClinVar as Benign. ClinVar VariationId is 258164.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0573 is higher than 0.05.

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.*11C>T		3_prime_UTR	Exon 3 of 3	NP_001531.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSPB1	ENST00000248553.7	TSL:1 MANE Select	c.*11C>T		3_prime_UTR	Exon 3 of 3	ENSP00000248553.6
	HSPB1	ENST00000429938.1	TSL:1	c.*11C>T		3_prime_UTR	Exon 3 of 3	ENSP00000405285.1
	HSPB1	ENST00000447574.1	TSL:1	n.1379C>T		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes AF: 0.0252 AC: 3833 AN: 152130 Hom.: 102 Cov.: 32

Gnomad AFR AF: 0.0594

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0220

Gnomad ASJ AF: 0.0375

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0232

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.142

Gnomad NFE AF: 0.0100

Gnomad OTH AF: 0.0292

GnomAD2 exomes AF: 0.0149 AC: 3388 AN: 226686 AF XY: 0.0143

Gnomad AFR exome AF: 0.0667

Gnomad AMR exome AF: 0.0140

Gnomad ASJ exome AF: 0.0394

Gnomad EAS exome AF: 0.000120

Gnomad FIN exome AF: 0.000758

Gnomad NFE exome AF: 0.00967

Gnomad OTH exome AF: 0.0182

GnomAD4 exome AF: 0.0117 AC: 17011 AN: 1452246 Hom.: 209 Cov.: 32 AF XY: 0.0118 AC XY: 8532 AN XY: 721830

African (AFR) AF: 0.0590 AC: 1954 AN: 33096

American (AMR) AF: 0.0140 AC: 613 AN: 43738

Ashkenazi Jewish (ASJ) AF: 0.0407 AC: 1057 AN: 25948

East Asian (EAS) AF: 0.0000513 AC: 2 AN: 38992

South Asian (SAS) AF: 0.0210 AC: 1782 AN: 84936

European-Finnish (FIN) AF: 0.000712 AC: 37 AN: 51996

Middle Eastern (MID) AF: 0.0436 AC: 250 AN: 5730

European-Non Finnish (NFE) AF: 0.00926 AC: 10254 AN: 1107862

Other (OTH) AF: 0.0177 AC: 1062 AN: 59948

GnomAD4 genome AF: 0.0251 AC: 3828 AN: 152248 Hom.: 100 Cov.: 32 AF XY: 0.0246 AC XY: 1830 AN XY: 74462

African (AFR) AF: 0.0592 AC: 2460 AN: 41542

American (AMR) AF: 0.0219 AC: 335 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0375 AC: 130 AN: 3470

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5166

South Asian (SAS) AF: 0.0230 AC: 111 AN: 4828

European-Finnish (FIN) AF: 0.000565 AC: 6 AN: 10622

Middle Eastern (MID) AF: 0.139 AC: 41 AN: 294

European-Non Finnish (NFE) AF: 0.0100 AC: 683 AN: 68004

Other (OTH) AF: 0.0289 AC: 61 AN: 2112

Alfa AF: 0.0198 Hom.: 30

Bravo AF: 0.0281

Asia WGS AF: 0.0110 AC: 37 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Charcot-Marie-Tooth disease (1)
-	-	1	Charcot-Marie-Tooth disease axonal type 2F (1)
-	-	1	Neuronopathy, distal hereditary motor, type 2B (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	6.0
DANN	Benign	0.88
PhyloP100		-2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1058872; hg19: chr7-75933501;