rs781279282

Variant names:

• chr2-197488488-C-T
• rs781279282
• NM_002156.5:c.1219G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PP3_Strong

The NM_002156.5(HSPD1):​c.1219G>A​(p.Gly407Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000753 in 1,461,086 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: HSPD1 NM_002156.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.46
• Publications: 0 publications found

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]

HSPD1 Gene-Disease associations (from GenCC):

• hereditary spastic paraplegia 13

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• hypomyelinating leukodystrophy 4

  Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet, Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.946

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002156.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSPD1	NM_002156.5	MANE Select	c.1219G>A	p.Gly407Ser	missense	Exon 10 of 12	NP_002147.2
	HSPD1	NM_199440.2		c.1219G>A	p.Gly407Ser	missense	Exon 10 of 12	NP_955472.1	A0A024R3X4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSPD1	ENST00000388968.8	TSL:1 MANE Select	c.1219G>A	p.Gly407Ser	missense	Exon 10 of 12	ENSP00000373620.3	P10809-1
	HSPD1	ENST00000954440.1		c.1267G>A	p.Gly423Ser	missense	Exon 10 of 12	ENSP00000624499.1
	HSPD1	ENST00000345042.6	TSL:5	c.1219G>A	p.Gly407Ser	missense	Exon 10 of 12	ENSP00000340019.2	P10809-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000797 AC: 2 AN: 250886 AF XY: 0.00000737

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000753 AC: 11 AN: 1461086 Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6 AN XY: 726906

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000720 AC: 8 AN: 1111296

Other (OTH) AF: 0.0000497 AC: 3 AN: 60354

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)
-	1	-	Spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Pathogenic	5.1	H
PhyloP100		7.5
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-5.6	D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.99	D
Vest4		0.92
MutPred		0.76		Gain of glycosylation at G407 (P = 0.0514)
MVP		0.87
MPC		1.7
ClinPred		1.0	D
GERP RS		5.3
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0
Varity_R		0.98
gMVP		0.96
Mutation Taster		=16/84	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs781279282; hg19: chr2-198353212;