rs61736612

Variant names:

• chr2-197489077-G-A
• rs61736612
• NM_002156.5:c.1140C>T

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.1140C>T​(p.Val380Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0109 in 1,613,686 control chromosomes in the GnomAD database, including 1,525 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.056 (782 hom., cov: 32)
  • Exomes 𝑓: 0.0062 (743 hom.)
• Consequence: HSPD1 NM_002156.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.648
• 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 2-197489077-G-A is Benign according to our data. Variant chr2-197489077-G-A is described in ClinVar as Benign. ClinVar VariationId is 137561.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.648 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.19 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.1140C>T	p.Val380Val	synonymous	Exon 9 of 12	NP_002147.2
	HSPD1	NM_199440.2		c.1140C>T	p.Val380Val	synonymous	Exon 9 of 12	NP_955472.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSPD1	ENST00000388968.8	TSL:1 MANE Select	c.1140C>T	p.Val380Val	synonymous	Exon 9 of 12	ENSP00000373620.3
	HSPD1	ENST00000954440.1		c.1188C>T	p.Val396Val	synonymous	Exon 9 of 12	ENSP00000624499.1
	HSPD1	ENST00000345042.6	TSL:5	c.1140C>T	p.Val380Val	synonymous	Exon 9 of 12	ENSP00000340019.2

Frequencies

GnomAD3 genomes AF: 0.0562 AC: 8551 AN: 152068 Hom.: 779 Cov.: 32

Gnomad AFR AF: 0.194

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0242

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00165

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000941

Gnomad OTH AF: 0.0440

GnomAD2 exomes AF: 0.0154 AC: 3866 AN: 251172 AF XY: 0.0115

Gnomad AFR exome AF: 0.200

Gnomad AMR exome AF: 0.0122

Gnomad ASJ exome AF: 0.00129

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000996

Gnomad OTH exome AF: 0.00930

GnomAD4 exome AF: 0.00621 AC: 9078 AN: 1461500 Hom.: 743 Cov.: 32 AF XY: 0.00531 AC XY: 3862 AN XY: 727084

African (AFR) AF: 0.199 AC: 6663 AN: 33462

American (AMR) AF: 0.0137 AC: 613 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00142 AC: 37 AN: 26128

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39694

South Asian (SAS) AF: 0.000510 AC: 44 AN: 86234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.0104 AC: 60 AN: 5758

European-Non Finnish (NFE) AF: 0.000711 AC: 790 AN: 1111716

Other (OTH) AF: 0.0144 AC: 870 AN: 60374

GnomAD4 genome AF: 0.0564 AC: 8580 AN: 152186 Hom.: 782 Cov.: 32 AF XY: 0.0547 AC XY: 4068 AN XY: 74408

African (AFR) AF: 0.194 AC: 8037 AN: 41456

American (AMR) AF: 0.0242 AC: 370 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000941 AC: 64 AN: 68022

Other (OTH) AF: 0.0436 AC: 92 AN: 2112

Alfa AF: 0.0180 Hom.: 87

Bravo AF: 0.0645

Asia WGS AF: 0.0120 AC: 42 AN: 3478

EpiCase AF: 0.000981

EpiControl AF: 0.00142

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	7.6
DANN	Benign	0.58
PhyloP100		0.65
Mutation Taster		=96/4	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: rs61736612; hg19: chr2-198353801;