rs8539

Variant names:

• chr2-197497294-T-C
• rs8539
• NM_002156.5:c.273A>G

Your query was ambiguous. Multiple possible variants found:

• chr2-197497294-T-C
• chr2-197497294-T-A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002156.5(HSPD1):​c.273A>G​(p.Lys91Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.666 in 1,612,620 control chromosomes in the GnomAD database, including 360,608 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.67 (34541 hom., cov: 33)
  • Exomes 𝑓: 0.67 (326067 hom.)
• Consequence: HSPD1 NM_002156.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.897
• Publications: 43 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 2-197497294-T-C is Benign according to our data. Variant chr2-197497294-T-C is described in ClinVar as Benign. ClinVar VariationId is 129241.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.897 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.71 is higher than 0.05.

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.273A>G	p.Lys91Lys	synonymous	Exon 3 of 12	NP_002147.2
	HSPD1	NM_199440.2		c.273A>G	p.Lys91Lys	synonymous	Exon 3 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.273A>G	p.Lys91Lys	synonymous	Exon 3 of 12	ENSP00000373620.3	P10809-1
	HSPD1	ENST00000954440.1		c.273A>G	p.Lys91Lys	synonymous	Exon 3 of 12	ENSP00000624499.1
	HSPD1	ENST00000345042.6	TSL:5	c.273A>G	p.Lys91Lys	synonymous	Exon 3 of 12	ENSP00000340019.2	P10809-1

Frequencies

GnomAD3 genomes AF: 0.671 AC: 101969 AN: 151992 Hom.: 34518 Cov.: 33

Gnomad AFR AF: 0.717

Gnomad AMI AF: 0.714

Gnomad AMR AF: 0.637

Gnomad ASJ AF: 0.744

Gnomad EAS AF: 0.503

Gnomad SAS AF: 0.683

Gnomad FIN AF: 0.571

Gnomad MID AF: 0.848

Gnomad NFE AF: 0.672

Gnomad OTH AF: 0.697

GnomAD2 exomes AF: 0.639 AC: 160735 AN: 251372 AF XY: 0.651

Gnomad AFR exome AF: 0.715

Gnomad AMR exome AF: 0.490

Gnomad ASJ exome AF: 0.747

Gnomad EAS exome AF: 0.512

Gnomad FIN exome AF: 0.577

Gnomad NFE exome AF: 0.680

Gnomad OTH exome AF: 0.688

GnomAD4 exome AF: 0.666 AC: 972323 AN: 1460510 Hom.: 326067 Cov.: 40 AF XY: 0.668 AC XY: 485304 AN XY: 726628

African (AFR) AF: 0.723 AC: 24180 AN: 33448

American (AMR) AF: 0.512 AC: 22876 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.743 AC: 19401 AN: 26126

East Asian (EAS) AF: 0.555 AC: 22024 AN: 39692

South Asian (SAS) AF: 0.696 AC: 60040 AN: 86238

European-Finnish (FIN) AF: 0.579 AC: 30934 AN: 53414

Middle Eastern (MID) AF: 0.842 AC: 4849 AN: 5762

European-Non Finnish (NFE) AF: 0.673 AC: 747628 AN: 1110758

Other (OTH) AF: 0.669 AC: 40391 AN: 60350

GnomAD4 genome AF: 0.671 AC: 102040 AN: 152110 Hom.: 34541 Cov.: 33 AF XY: 0.668 AC XY: 49640 AN XY: 74360

African (AFR) AF: 0.717 AC: 29734 AN: 41484

American (AMR) AF: 0.636 AC: 9732 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.744 AC: 2581 AN: 3468

East Asian (EAS) AF: 0.504 AC: 2604 AN: 5168

South Asian (SAS) AF: 0.684 AC: 3298 AN: 4824

European-Finnish (FIN) AF: 0.571 AC: 6035 AN: 10578

Middle Eastern (MID) AF: 0.850 AC: 250 AN: 294

European-Non Finnish (NFE) AF: 0.672 AC: 45689 AN: 67978

Other (OTH) AF: 0.694 AC: 1466 AN: 2112

Alfa AF: 0.679 Hom.: 15351

Bravo AF: 0.676

Asia WGS AF: 0.591 AC: 2060 AN: 3478

EpiCase AF: 0.706

EpiControl AF: 0.707

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	Hereditary spastic paraplegia 13 (2)
-	-	1	Hereditary spastic paraplegia (1)
-	-	1	Hypomyelinating leukodystrophy 4 (1)
-	-	1	not provided (1)
-	-	1	Spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	8.8
DANN	Benign	0.88
PhyloP100		0.90
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs8539; hg19: chr2-198362018; COSMIC: COSV52098444; COSMIC: COSV52098444;