rs3749095

Variant names:

• chr2-197499794-G-A
• rs13165
• NM_002156.5:c.-15C>T

Variant summary

Our verdict is Benign. The variant received -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 premature start codon gain 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_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.243
• Publications: 8 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: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
• hypomyelinating leukodystrophy 4

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

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 137567.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.334 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.-15C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 12	NP_002147.2
	HSPD1	NM_002156.5	MANE Select	c.-15C>T		5_prime_UTR	Exon 1 of 12	NP_002147.2
	HSPD1	NM_199440.2		c.-3+366C>T		intron	N/A	NP_955472.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSPD1	ENST00000388968.8	TSL:1 MANE Select	c.-15C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 12	ENSP00000373620.3
	HSPD1	ENST00000388968.8	TSL:1 MANE Select	c.-15C>T		5_prime_UTR	Exon 1 of 12	ENSP00000373620.3
	HSPD1	ENST00000954440.1		c.-15C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 12	ENSP00000624499.1

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

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 4

East Asian (EAS) AF: 0.00 AC: 0 AN: 2

South Asian (SAS) AF: 0.00 AC: 0 AN: 6

European-Finnish (FIN) AF: 0.167 AC: 2 AN: 12

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.0682 AC: 3 AN: 44

Other (OTH) AF: 0.333 AC: 2 AN: 6

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

African (AFR) AF: 0.339 AC: 14057 AN: 41500

American (AMR) AF: 0.224 AC: 3430 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.236 AC: 819 AN: 3468

East Asian (EAS) AF: 0.236 AC: 1216 AN: 5152

South Asian (SAS) AF: 0.120 AC: 577 AN: 4828

European-Finnish (FIN) AF: 0.184 AC: 1956 AN: 10612

Middle Eastern (MID) AF: 0.296 AC: 87 AN: 294

European-Non Finnish (NFE) AF: 0.188 AC: 12815 AN: 67988

Other (OTH) AF: 0.248 AC: 522 AN: 2108

Alfa AF: 0.209 Hom.: 429

Bravo AF: 0.246

Asia WGS AF: 0.189 AC: 658 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	16
DANN	Benign	0.88
PhyloP100		-0.24
PromoterAI		0.0064	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		3.6
Mutation Taster		=300/0	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: rs13165; hg19: chr2-198364518;