chr9-136423619-A-G

Variant names:

• chr9-136423619-A-G
• rs7628
• NM_015160.3:c.*355A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_015160.3(PMPCA):​c.*355A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.438 in 258,716 control chromosomes in the GnomAD database, including 26,201 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.42 (14151 hom., cov: 32)
  • Exomes 𝑓: 0.46 (12050 hom.)
• Consequence: PMPCA NM_015160.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.51
• Publications: 17 publications found

Genes affected

PMPCA (HGNC:18667): (peptidase, mitochondrial processing subunit alpha) The protein encoded by this gene is found in the mitochondrion, where it represents the alpha subunit of a proteolytic heterodimer. This heterodimer is responsible for cleaving the transit peptide from nuclear-encoded mitochondrial proteins. Defects in this gene are a cause of spinocerebellar ataxia, autosomal recessive 2. [provided by RefSeq, Mar 2016]

PMPCA Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• autosomal recessive spinocerebellar ataxia 2

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.523 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PMPCA	NM_015160.3	c.*355A>G		3_prime_UTR_variant	Exon 13 of 13	ENST00000371717.8	NP_055975.1
PMPCA	NM_001282946.2	c.*355A>G		3_prime_UTR_variant	Exon 13 of 13		NP_001269875.1
PMPCA	NM_001282944.2	c.*355A>G		3_prime_UTR_variant	Exon 12 of 12		NP_001269873.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PMPCA	ENST00000371717.8	c.*355A>G		3_prime_UTR_variant	Exon 13 of 13	1	NM_015160.3	ENSP00000360782.3

Frequencies

GnomAD3 genomes AF: 0.421 AC: 64001 AN: 151858 Hom.: 14128 Cov.: 32

Gnomad AFR AF: 0.295

Gnomad AMI AF: 0.499

Gnomad AMR AF: 0.532

Gnomad ASJ AF: 0.494

Gnomad EAS AF: 0.302

Gnomad SAS AF: 0.388

Gnomad FIN AF: 0.374

Gnomad MID AF: 0.386

Gnomad NFE AF: 0.487

Gnomad OTH AF: 0.445

GnomAD4 exome AF: 0.463 AC: 49381 AN: 106740 Hom.: 12050 Cov.: 0 AF XY: 0.458 AC XY: 25622 AN XY: 55960

African (AFR) AF: 0.289 AC: 1350 AN: 4678

American (AMR) AF: 0.565 AC: 3400 AN: 6016

Ashkenazi Jewish (ASJ) AF: 0.507 AC: 1570 AN: 3096

East Asian (EAS) AF: 0.308 AC: 2064 AN: 6712

South Asian (SAS) AF: 0.374 AC: 4684 AN: 12540

European-Finnish (FIN) AF: 0.383 AC: 1552 AN: 4052

Middle Eastern (MID) AF: 0.426 AC: 196 AN: 460

European-Non Finnish (NFE) AF: 0.503 AC: 31886 AN: 63336

Other (OTH) AF: 0.458 AC: 2679 AN: 5850

GnomAD4 genome AF: 0.422 AC: 64063 AN: 151976 Hom.: 14151 Cov.: 32 AF XY: 0.416 AC XY: 30918 AN XY: 74274

African (AFR) AF: 0.295 AC: 12226 AN: 41472

American (AMR) AF: 0.533 AC: 8142 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.494 AC: 1714 AN: 3470

East Asian (EAS) AF: 0.301 AC: 1543 AN: 5126

South Asian (SAS) AF: 0.388 AC: 1871 AN: 4824

European-Finnish (FIN) AF: 0.374 AC: 3956 AN: 10564

Middle Eastern (MID) AF: 0.391 AC: 115 AN: 294

European-Non Finnish (NFE) AF: 0.487 AC: 33103 AN: 67928

Other (OTH) AF: 0.447 AC: 939 AN: 2102

Alfa AF: 0.472 Hom.: 10271

Bravo AF: 0.427

Asia WGS AF: 0.411 AC: 1429 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.49
DANN	Benign	0.39
PhyloP100		-1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	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: rs7628; hg19: chr9-139318071;