2-197500350-A-AT

Position:

• chr2-197500350-A-AT

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The ENST00000409729.1(HSPE1):​c.-87_-86insT variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00151 in 1,554,994 control chromosomes in the GnomAD database, including 15 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0052 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (8 hom.)
• Consequence: HSPE1 ENST00000409729.1 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.72

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]

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]

HSPE1 (HGNC:):

HSPE1-MOB4 (HGNC:49184): (HSPE1-MOB4 readthrough) This locus represents naturally occurring read-through transcription between the neighboring HSPE1 (heat shock 10kDa protein 1 (chaperonin 10)) and MOB4 (MOB family member 4, phocein) genes on chromosome 2. The read-through transcript produces a fusion protein that shares sequence identity with each individual gene product. [provided by RefSeq, Oct 2011]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP6: Variant 2-197500350-A-AT is Benign according to our data. Variant chr2-197500350-A-AT is described in ClinVar as [Likely_benign]. Clinvar id is 1206817.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.00112 (1565/1402982) while in subpopulation AFR AF= 0.0171 (547/31910). AF 95% confidence interval is 0.016. There are 8 homozygotes in gnomad4_exome. There are 763 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 788 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
		n.197500350_197500351insT		intergenic_region
HSPE1	NM_002157.3	c.-87_-86insT		upstream_gene_variant		ENST00000233893.10	NP_002148.1
HSPE1-MOB4	NM_001202485.2	c.-87_-86insT		upstream_gene_variant			NP_001189414.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HSPE1	ENST00000233893.10	c.-87_-86insT		upstream_gene_variant		1	NM_002157.3	ENSP00000233893.5

Frequencies

GnomAD3 genomes AF: 0.00516 AC: 784 AN: 151894 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.0154

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00465

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.000585

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000736

Gnomad OTH AF: 0.00335

GnomAD4 exome AF: 0.00112 AC: 1565 AN: 1402982 Hom.: 8 Cov.: 31 AF XY: 0.00110 AC XY: 763 AN XY: 692480

Gnomad4 AFR exome AF: 0.0171

Gnomad4 AMR exome AF: 0.00192

Gnomad4 ASJ exome AF: 0.00222

Gnomad4 EAS exome AF: 0.000466

Gnomad4 SAS exome AF: 0.00172

Gnomad4 FIN exome AF: 0.0000203

Gnomad4 NFE exome AF: 0.000549

Gnomad4 OTH exome AF: 0.00205

GnomAD4 genome AF: 0.00518 AC: 788 AN: 152012 Hom.: 7 Cov.: 32 AF XY: 0.00510 AC XY: 379 AN XY: 74314

Gnomad4 AFR AF: 0.0155

Gnomad4 AMR AF: 0.00464

Gnomad4 ASJ AF: 0.00231

Gnomad4 EAS AF: 0.000586

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000736

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00481 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 29, 2018

- -

Computational scores

Source: dbNSFP v4.3

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: rs564376869; hg19: chr2-198365074;