2-197503117-C-A

Position:

• chr2-197503117-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002157.3(HSPE1):​c.247C>A​(p.Leu83Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HSPE1 NM_002157.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.86

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: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]

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:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24393135).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HSPE1	NM_002157.3	c.247C>A	p.Leu83Ile	missense_variant	3/4	ENST00000233893.10	NP_002148.1
HSPE1-MOB4	NM_001202485.2	c.168+1879C>A		intron_variant			NP_001189414.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HSPE1	ENST00000233893.10	c.247C>A	p.Leu83Ile	missense_variant	3/4	1	NM_002157.3	ENSP00000233893.5
HSPE1-MOB4	ENST00000604458.1	c.168+1879C>A		intron_variant		3		ENSP00000474534.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.90e-7 AC: 1 AN: 1449658 Hom.: 0 Cov.: 27 AF XY: 0.00000138 AC XY: 1 AN XY: 722056

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.08e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 29, 2024

The c.247C>A (p.L83I) alteration is located in exon 3 (coding exon 3) of the HSPE1 gene. This alteration results from a C to A substitution at nucleotide position 247, causing the leucine (L) at amino acid position 83 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.040	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.19	T;.;T
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.80	T;T;T
M_CAP	Benign	0.0037	T
MetaRNN	Benign	0.24	T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.45	N;.;.
PROVEAN	Benign	-0.89	N;N;N
REVEL	Uncertain	0.29
Sift	Benign	0.082	T;T;T
Sift4G	Benign	0.29	T;T;T
Polyphen		0.98	D;.;.
Vest4		0.29
MutPred		0.46		Loss of catalytic residue at L83 (P = 0.0154);.;Loss of catalytic residue at L83 (P = 0.0154);
MVP		0.57
MPC		1.2
ClinPred		0.59	D
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.42
gMVP		0.64

Splicing

Name	Calibrated prediction	Score	Prediction
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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-198367841;