2-197503087-C-T

Position:

• chr2-197503087-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_002157.3(HSPE1):​c.217C>T​(p.Leu73Phe) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: HSPE1 NM_002157.3 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 3.02

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.744

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HSPE1	NM_002157.3	c.217C>T	p.Leu73Phe	missense_variant	3/4	ENST00000233893.10	NP_002148.1
HSPE1-MOB4	NM_001202485.2	c.168+1849C>T		intron_variant			NP_001189414.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HSPE1	ENST00000233893.10	c.217C>T	p.Leu73Phe	missense_variant	3/4	1	NM_002157.3	ENSP00000233893.5
HSPE1-MOB4	ENST00000604458.1	c.168+1849C>T		intron_variant		3		ENSP00000474534.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

OMIM

Jul 24, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.46	T;.;T
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Benign	0.0054	T
MetaRNN	Pathogenic	0.74	D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.47	N;.;.
PROVEAN	Uncertain	-3.5	D;D;D
REVEL	Uncertain	0.40
Sift	Uncertain	0.0010	D;D;D
Sift4G	Benign	0.29	T;T;T
Polyphen		0.95	P;.;.
Vest4		0.75
MutPred		0.57		Gain of methylation at K70 (P = 0.0669);.;Gain of methylation at K70 (P = 0.0669);
MVP		0.75
MPC		1.8
ClinPred		0.99	D
GERP RS		5.1
Varity_R		0.83
gMVP		0.81

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: rs1574610140; hg19: chr2-198367811;