rs2305560

chr2-197501064-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002157.3(HSPE1):c.4-10C>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.17 in 1,602,078 control chromosomes in the GnomAD database, including 24,327 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.15 (1897 hom., cov: 32)
  • Exomes 𝑓: 0.17 (22430 hom.)
• Consequence: HSPE1 NM_002157.3 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00008184
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.316

Genes affected

HSPE1 (HGNC:5269): (heat shock protein family E (Hsp10) member 1) This gene encodes a major heat shock protein which functions as a chaperonin. Its structure consists of a heptameric ring which binds to another heat shock protein in order to form a symmetric, functional heterodimer which enhances protein folding in an ATP-dependent manner. This gene and its co-chaperonin, HSPD1, are arranged in a head-to-head orientation on chromosome 2. Naturally occurring read-through transcription occurs between this locus and the neighboring locus MOBKL3.[provided by RefSeq, Feb 2011]

HSPE1-MOB4 (HGNC:):

HSPD1 (HGNC:5261): (heat shock protein family D (Hsp60) member 1) This gene encodes a member of the chaperonin family. The encoded mitochondrial protein may function as a signaling molecule in the innate immune system. This protein is essential for the folding and assembly of newly imported proteins in the mitochondria. This gene is adjacent to a related family member and the region between the 2 genes functions as a bidirectional promoter. Several pseudogenes have been associated with this gene. Two transcript variants encoding the same protein have been identified for this gene. Mutations associated with this gene cause autosomal recessive spastic paraplegia 13. [provided by RefSeq, Jun 2010]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.219 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HSPE1	NM_002157.3	c.4-10C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000233893.10
HSPE1-MOB4	NM_001202485.2	c.4-10C>T		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HSPE1	ENST00000233893.10	c.4-10C>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_002157.3	P1

Frequencies

GnomAD3 genomes AF: 0.146 AC: 22251 AN: 152074 Hom.: 1894 Cov.: 32

Gnomad AFR AF: 0.0613

Gnomad AMI AF: 0.195

Gnomad AMR AF: 0.186

Gnomad ASJ AF: 0.235

Gnomad EAS AF: 0.229

Gnomad SAS AF: 0.0925

Gnomad FIN AF: 0.178

Gnomad MID AF: 0.266

Gnomad NFE AF: 0.175

Gnomad OTH AF: 0.174

GnomAD3 exomes AF: 0.167 AC: 41013 AN: 246078 Hom.: 3769 AF XY: 0.167 AC XY: 22188 AN XY: 133214

Gnomad AFR exome AF: 0.0572

Gnomad AMR exome AF: 0.190

Gnomad ASJ exome AF: 0.232

Gnomad EAS exome AF: 0.234

Gnomad SAS exome AF: 0.0900

Gnomad FIN exome AF: 0.177

Gnomad NFE exome AF: 0.175

Gnomad OTH exome AF: 0.196

GnomAD4 exome AF: 0.173 AC: 250308 AN: 1449886 Hom.: 22430 Cov.: 31 AF XY: 0.171 AC XY: 123415 AN XY: 720836

Gnomad4 AFR exome AF: 0.0541

Gnomad4 AMR exome AF: 0.189

Gnomad4 ASJ exome AF: 0.237

Gnomad4 EAS exome AF: 0.229

Gnomad4 SAS exome AF: 0.0925

Gnomad4 FIN exome AF: 0.178

Gnomad4 NFE exome AF: 0.178

Gnomad4 OTH exome AF: 0.172

GnomAD4 genome AF: 0.146 AC: 22262 AN: 152192 Hom.: 1897 Cov.: 32 AF XY: 0.148 AC XY: 10979 AN XY: 74396

Gnomad4 AFR AF: 0.0612

Gnomad4 AMR AF: 0.186

Gnomad4 ASJ AF: 0.235

Gnomad4 EAS AF: 0.230

Gnomad4 SAS AF: 0.0943

Gnomad4 FIN AF: 0.178

Gnomad4 NFE AF: 0.175

Gnomad4 OTH AF: 0.173

Alfa AF: 0.162 Hom.: 879

Bravo AF: 0.148

Asia WGS AF: 0.138 AC: 481 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
Cadd	Benign	6.7
Dann	Benign	0.86

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000082
dbscSNV1_RF	Benign	0.0080
SpliceAI score (max)		0.040		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: rs2305560; hg19: chr2-198365788; COSMIC: COSV52098936; COSMIC: COSV52098936;