2-197487052-C-T

Variant names:

• chr2-197487052-C-T
• rs1559299819
• NM_002156.5:c.1716G>A

Variant summary

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

The NM_002156.5(HSPD1):​c.1716G>A​(p.Met572Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000023 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HSPD1 NM_002156.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.20

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]

SNORA105B (HGNC:51398): (small nucleolar RNA, H/ACA box 105B)

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSPD1	NM_002156.5	c.1716G>A	p.Met572Ile	missense_variant	Exon 12 of 12	ENST00000388968.8	NP_002147.2
HSPD1	NM_199440.2	c.1716G>A	p.Met572Ile	missense_variant	Exon 12 of 12		NP_955472.1
SNORA105B	NR_132788.1	n.-149G>A		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HSPD1	ENST00000388968.8	c.1716G>A	p.Met572Ile	missense_variant	Exon 12 of 12	1	NM_002156.5	ENSP00000373620.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000233 AC: 3 AN: 1290168 Hom.: 0 Cov.: 19 AF XY: 0.00000307 AC XY: 2 AN XY: 650628

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: 0.00000209

Gnomad4 OTH exome AF: 0.0000183

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Dec 28, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1716G>A (p.M572I) alteration is located in exon 12 (coding exon 11) of the HSPD1 gene. This alteration results from a G to A substitution at nucleotide position 1716, causing the methionine (M) at amino acid position 572 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	Uncertain	0.56
BayesDel_addAF	Uncertain	0.024	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.77	D;D
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.84	.;T
M_CAP	Benign	0.052	D
MetaRNN	Uncertain	0.43	T;T
MetaSVM	Benign	-0.38	T
MutationAssessor	Benign	1.9	L;L
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-2.2	N;N
REVEL	Uncertain	0.36
Sift	Benign	0.053	T;T
Sift4G	Uncertain	0.0040	D;D
Polyphen		0.0	B;B
Vest4		0.63
MutPred		0.26		Gain of catalytic residue at M572 (P = 0.0987);Gain of catalytic residue at M572 (P = 0.0987);
MVP		0.38
MPC		2.1
ClinPred		0.91	D
GERP RS		5.2
Varity_R		0.38
gMVP		0.76

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: rs1559299819; hg19: chr2-198351776;