rs1553577750

Positions:

• chr2-197488383-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_002156.5(HSPD1):​c.1324T>C​(p.Cys442Arg) variant causes a missense change. 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 (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: HSPD1 NM_002156.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 6.92

Genes affected

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.966

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HSPD1	NM_002156.5	c.1324T>C	p.Cys442Arg	missense_variant	10/12	ENST00000388968.8
HSPD1	NM_199440.2	c.1324T>C	p.Cys442Arg	missense_variant	10/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HSPD1	ENST00000388968.8	c.1324T>C	p.Cys442Arg	missense_variant	10/12	1	NM_002156.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Spastic paraplegia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 16, 2017

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with HSPD1-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces cysteine with arginine at codon 442 of the HSPD1 protein (p.Cys442Arg). The cysteine residue is moderately conserved and there is a large physicochemical difference between cysteine and arginine. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 20, 2023

The c.1324T>C (p.C442R) alteration is located in exon 10 (coding exon 9) of the HSPD1 gene. This alteration results from a T to C substitution at nucleotide position 1324, causing the cysteine (C) at amino acid position 442 to be replaced by an arginine (R). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. 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	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D;D
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.97	D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Uncertain	0.21	D
MutationAssessor	Uncertain	2.0	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-3.7	D;D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0050	D;D
Sift4G	Uncertain	0.0030	D;D
Polyphen		0.94	P;P
Vest4		0.91
MutPred		0.85		Gain of methylation at C442 (P = 0.0093);Gain of methylation at C442 (P = 0.0093);
MVP		0.93
MPC		2.1
ClinPred		0.99	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.99
gMVP		0.96

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: rs1553577750; hg19: chr2-198353107;