rs368936457

Variant names:

• chr7-76303797-C-A
• rs368936457
• ENST00000447574.1:n.1110C>A

Your query was ambiguous. Multiple possible variants found:

• chr7-76303797-C-A
• chr7-76303797-C-G
• chr7-76303797-C-T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The ENST00000447574.1(HSPB1):​n.1110C>A variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000823 in 1,458,586 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: HSPB1 ENST00000447574.1 non_coding_transcript_exon
• Scores: Splicing: ADA: 0.0004944
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.409
• Publications: 0 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 7-76303797-C-A is Benign according to our data. Variant chr7-76303797-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1733625.
• BS2: High AC in GnomAdExome4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSPB1	NM_001540.5	c.365-5C>A		splice_region_variant, intron_variant	Intron 1 of 2	ENST00000248553.7	NP_001531.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HSPB1	ENST00000248553.7	c.365-5C>A		splice_region_variant, intron_variant	Intron 1 of 2	1	NM_001540.5	ENSP00000248553.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000804 AC: 2 AN: 248694 AF XY: 0.00000739

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000179

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000823 AC: 12 AN: 1458586 Hom.: 0 Cov.: 32 AF XY: 0.00000965 AC XY: 7 AN XY: 725604

African (AFR) AF: 0.00 AC: 0 AN: 33396

American (AMR) AF: 0.00 AC: 0 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 86156

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52562

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4160

European-Non Finnish (NFE) AF: 0.00000990 AC: 11 AN: 1111604

Other (OTH) AF: 0.00 AC: 0 AN: 60190

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Dec 19, 2019

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.365-5C>A intronic variant results from a C to A substitution 5 nucleotides upstream from coding exon 2 in the HSPB1 gene. This nucleotide position is not well conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to weaken the efficiency of the native splice acceptor site; however, direct evidence is unavailable. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

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

May 20, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	3.9
DANN	Benign	0.64
PhyloP100		0.41
PromoterAI		0.049	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00049
dbscSNV1_RF	Benign	0.068
SpliceAI score (max)		0.010		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: rs368936457; hg19: chr7-75933114;