rs3749095

Positions:

• chr2-197499794-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002156.5(HSPD1):​c.-15C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.234 in 152,230 control chromosomes in the GnomAD database, including 4,576 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4575 hom., cov: 33)
  • Exomes 𝑓: 0.095 (1 hom.)
• Consequence: HSPD1 NM_002156.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.243

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 2-197499794-G-A is Benign according to our data. Variant chr2-197499794-G-A is described in ClinVar as [Benign]. Clinvar id is 137567.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-197499794-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.334 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HSPD1	NM_002156.5	c.-15C>T		5_prime_UTR_variant	1/12	ENST00000388968.8	NP_002147.2
HSPD1	NM_199440.2	c.-3+366C>T		intron_variant			NP_955472.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HSPD1	ENST00000388968.8	c.-15C>T		5_prime_UTR_variant	1/12	1	NM_002156.5	ENSP00000373620	P1

Frequencies

GnomAD3 genomes AF: 0.234 AC: 35592 AN: 152038 Hom.: 4558 Cov.: 33

Gnomad AFR AF: 0.338

Gnomad AMI AF: 0.197

Gnomad AMR AF: 0.225

Gnomad ASJ AF: 0.236

Gnomad EAS AF: 0.235

Gnomad SAS AF: 0.118

Gnomad FIN AF: 0.184

Gnomad MID AF: 0.291

Gnomad NFE AF: 0.189

Gnomad OTH AF: 0.246

GnomAD4 exome AF: 0.0946 AC: 7 AN: 74 Hom.: 1 Cov.: 0 AF XY: 0.0806 AC XY: 5 AN XY: 62

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.167

Gnomad4 NFE exome AF: 0.0682

Gnomad4 OTH exome AF: 0.333

GnomAD4 genome AF: 0.234 AC: 35658 AN: 152156 Hom.: 4575 Cov.: 33 AF XY: 0.233 AC XY: 17328 AN XY: 74382

Gnomad4 AFR AF: 0.339

Gnomad4 AMR AF: 0.224

Gnomad4 ASJ AF: 0.236

Gnomad4 EAS AF: 0.236

Gnomad4 SAS AF: 0.120

Gnomad4 FIN AF: 0.184

Gnomad4 NFE AF: 0.188

Gnomad4 OTH AF: 0.248

Alfa AF: 0.209 Hom.: 429

Bravo AF: 0.246

Asia WGS AF: 0.189 AC: 658 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 05, 2013

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Hereditary spastic paraplegia 13 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	16
DANN	Benign	0.88
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		3.6

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

Publications

LitVar

Other links and lift over

dbSNP: rs13165; hg19: chr2-198364518;