NM_002156.5:c.428-10G>A

Variant names:

• chr2-197495386-C-T
• rs111401572
• NM_002156.5:c.428-10G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002156.5(HSPD1):​c.428-10G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00258 in 1,523,648 control chromosomes in the GnomAD database, including 78 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (41 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (37 hom.)
• Consequence: HSPD1 NM_002156.5 intron
• Scores: Splicing: ADA: 0.00007913
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.131
• Publications: 3 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 2-197495386-C-T is Benign according to our data. Variant chr2-197495386-C-T is described in ClinVar as Benign. ClinVar VariationId is 137566.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0125 (1904/151916) while in subpopulation AFR AF = 0.0439 (1817/41392). AF 95% confidence interval is 0.0422. There are 41 homozygotes in GnomAd4. There are 907 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 41 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.428-10G>A		intron	N/A	NP_002147.2
	HSPD1	NM_199440.2		c.428-10G>A		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.428-10G>A		intron	N/A	ENSP00000373620.3
	HSPD1	ENST00000954440.1		c.466G>A	p.Val156Ile	missense	Exon 4 of 12	ENSP00000624499.1
	HSPD1	ENST00000345042.6	TSL:5	c.428-10G>A		intron	N/A	ENSP00000340019.2

Frequencies

GnomAD3 genomes AF: 0.0125 AC: 1897 AN: 151800 Hom.: 41 Cov.: 32

Gnomad AFR AF: 0.0439

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00374

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00910

GnomAD2 exomes AF: 0.00345 AC: 866 AN: 251326 AF XY: 0.00251

Gnomad AFR exome AF: 0.0460

Gnomad AMR exome AF: 0.00257

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000132

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00148 AC: 2025 AN: 1371732 Hom.: 37 Cov.: 23 AF XY: 0.00126 AC XY: 867 AN XY: 687740

African (AFR) AF: 0.0476 AC: 1507 AN: 31652

American (AMR) AF: 0.00300 AC: 134 AN: 44620

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25574

East Asian (EAS) AF: 0.00 AC: 0 AN: 39242

South Asian (SAS) AF: 0.000130 AC: 11 AN: 84466

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53384

Middle Eastern (MID) AF: 0.00286 AC: 16 AN: 5590

European-Non Finnish (NFE) AF: 0.000152 AC: 157 AN: 1029814

Other (OTH) AF: 0.00348 AC: 200 AN: 57390

GnomAD4 genome AF: 0.0125 AC: 1904 AN: 151916 Hom.: 41 Cov.: 32 AF XY: 0.0122 AC XY: 907 AN XY: 74206

African (AFR) AF: 0.0439 AC: 1817 AN: 41392

American (AMR) AF: 0.00374 AC: 57 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10502

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 67982

Other (OTH) AF: 0.00900 AC: 19 AN: 2110

Alfa AF: 0.0101 Hom.: 14

Bravo AF: 0.0144

Asia WGS AF: 0.00115 AC: 5 AN: 3478

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 (1)
-	-	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	-0.79
CADD	Benign	7.2
DANN	Benign	0.64
PhyloP100		0.13
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000079
dbscSNV1_RF	Benign	0.0080
SpliceAI score (max)		0.010		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: rs111401572; hg19: chr2-198360110;