NM_002156.5:c.561T>C

Variant names:

• chr2-197494702-A-G
• rs141357756
• NM_002156.5:c.561T>C

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_002156.5(HSPD1):​c.561T>C​(p.Ser187Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00258 in 1,612,736 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (13 hom.)
• Consequence: HSPD1 NM_002156.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.106
• 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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 2-197494702-A-G is Benign according to our data. Variant chr2-197494702-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 214549.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.106 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 13 AR,AD gene

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.561T>C	p.Ser187Ser	synonymous	Exon 5 of 12	NP_002147.2
	HSPD1	NM_199440.2		c.561T>C	p.Ser187Ser	synonymous	Exon 5 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.561T>C	p.Ser187Ser	synonymous	Exon 5 of 12	ENSP00000373620.3	P10809-1
	HSPD1	ENST00000954440.1		c.609T>C	p.Ser203Ser	synonymous	Exon 5 of 12	ENSP00000624499.1
	HSPD1	ENST00000345042.6	TSL:5	c.561T>C	p.Ser187Ser	synonymous	Exon 5 of 12	ENSP00000340019.2	P10809-1

Frequencies

GnomAD3 genomes AF: 0.00151 AC: 230 AN: 152224 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00546

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00210

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00156 AC: 393 AN: 251382 AF XY: 0.00162

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00370

Gnomad NFE exome AF: 0.00252

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.00269 AC: 3923 AN: 1460394 Hom.: 13 Cov.: 29 AF XY: 0.00259 AC XY: 1881 AN XY: 726602

African (AFR) AF: 0.000269 AC: 9 AN: 33446

American (AMR) AF: 0.000335 AC: 15 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39628

South Asian (SAS) AF: 0.0000812 AC: 7 AN: 86218

European-Finnish (FIN) AF: 0.00386 AC: 206 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00322 AC: 3576 AN: 1110748

Other (OTH) AF: 0.00181 AC: 109 AN: 60344

GnomAD4 genome AF: 0.00151 AC: 230 AN: 152342 Hom.: 0 Cov.: 32 AF XY: 0.00166 AC XY: 124 AN XY: 74508

African (AFR) AF: 0.000529 AC: 22 AN: 41578

American (AMR) AF: 0.000327 AC: 5 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00546 AC: 58 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00210 AC: 143 AN: 68034

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.00215 Hom.: 0

Bravo AF: 0.00121

EpiCase AF: 0.00207

EpiControl AF: 0.00362

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Hereditary spastic paraplegia (1)
-	-	1	Hereditary spastic paraplegia 13 (1)
-	-	1	Hereditary spastic paraplegia 13;C2677109:Hypomyelinating leukodystrophy 4 (1)
-	-	1	HSPD1-related disorder (1)
-	-	1	not specified (1)
-	-	1	Spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	8.4
DANN	Benign	0.75
PhyloP100		0.11
Mutation Taster		=95/5	polymorphism

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: rs141357756; hg19: chr2-198359426;