rs72466451

Variant names:

• chr2-197498763-T-C
• rs72466451
• NM_002156.5:c.86A>G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Moderate PP5_Moderate

The NM_002156.5(HSPD1):​c.86A>G​(p.Asp29Gly) variant causes a missense change involving the alteration of a 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 Pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: HSPD1 NM_002156.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.99

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, 0.881
• PP5: Variant 2-197498763-T-C is Pathogenic according to our data. Variant chr2-197498763-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 17558.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSPD1	NM_002156.5	c.86A>G	p.Asp29Gly	missense_variant	Exon 2 of 12	ENST00000388968.8	NP_002147.2
HSPD1	NM_199440.2	c.86A>G	p.Asp29Gly	missense_variant	Exon 2 of 12		NP_955472.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HSPD1	ENST00000388968.8	c.86A>G	p.Asp29Gly	missense_variant	Exon 2 of 12	1	NM_002156.5	ENSP00000373620.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Hypomyelinating leukodystrophy 4 Pathogenic:1

Jul 01, 2008

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Leukodystrophy Pathogenic:1

Jan 13, 2025

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed in a homozygous state, at our lab, in a patient with matching phenotype. ACMG criteria used: PS3 (PMID: 18571143, 19706612, 25957474), PM2, PM3_Supporting, PP1_Strong (PMID: 18571143), PP3 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	D;D;T;T;.;.;T;T
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Pathogenic	0.98	.;D;D;D;D;D;D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.88	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.11	D
MutationAssessor	Pathogenic	3.2	M;M;.;.;.;.;.;.
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-4.4	D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.77
Sift	Benign	0.051	T;T;T;T;D;D;D;D
Sift4G	Uncertain	0.041	D;D;.;D;D;D;.;.
Polyphen		0.0020	B;B;.;.;.;.;.;.
Vest4		0.95
MutPred		0.78		Gain of MoRF binding (P = 0.0241);Gain of MoRF binding (P = 0.0241);Gain of MoRF binding (P = 0.0241);Gain of MoRF binding (P = 0.0241);.;Gain of MoRF binding (P = 0.0241);Gain of MoRF binding (P = 0.0241);Gain of MoRF binding (P = 0.0241);
MVP		0.89
MPC		0.93
ClinPred		0.99	D
GERP RS		4.9
Varity_R		0.75
gMVP		0.80

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

LitVar

Other links and lift over

dbSNP: rs72466451; hg19: chr2-198363487;