rs963172852

Positions:

chr9-136418848-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP5_Moderate

The NM_015160.3(PMPCA):c.1130C>T(p.Ala377Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000155 in 1,612,730 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

PMPCA
NM_015160.3 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 7.52

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 9-136418848-C-T is Pathogenic according to our data. Variant chr9-136418848-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 521567.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PMPCA	NM_015160.3 linkuse as main transcript	c.1130C>T	p.Ala377Val	missense_variant	10/13	ENST00000371717.8	NP_055975.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PMPCA	ENST00000371717.8 linkuse as main transcript	c.1130C>T	p.Ala377Val	missense_variant	10/13	1	NM_015160.3	ENSP00000360782	P1	Q10713-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000798

AC:

AN:

250722

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135598

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000144

AC:

AN:

1460436

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

726604

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000171

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152294

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000855

Hom.:

Bravo

AF:

0.0000227

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 03, 2024

The c.1130C>T (p.A377V) alteration is located in exon 10 (coding exon 10) of the PMPCA gene. This alteration results from a C to T substitution at nucleotide position 1130, causing the alanine (A) at amino acid position 377 to be replaced by a valine (V). Based on data from gnomAD, the T allele has an overall frequency of 0.001% (3/282114) total alleles studied. The highest observed frequency was 0.005% (1/19950) of East Asian alleles. Another alteration at the same codon, c.1129G>A (p.A377T), has been reported in the homozygous state in multiple Lebanese individuals with cerebellar ataxia, intellectual disability, dysarthria, and abnormal deep tendon reflexes (Jobling, 2015). The c.1129G>A (p.A377T) alteration has also been identified in trans with another PMPCA alteration in two individuals from a large Lebanese family with a more severe mitochondrial disorder (Joshi, 2016). Analysis of lymphoblastoid cells and fibroblasts from patients homozygous for the c.1129G>A (p.A377T) alteration revealed that this alteration affects the level of alpha subunit encoded as well as the overall function of mitochondrial processing peptidase (Jobling, 2015). This amino acid position is highly conserved in available vertebrate species. The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.88

BayesDel_addAF

Benign

0.010

BayesDel_noAF

Uncertain

-0.050

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.30

T;.;.

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.97

D;D;D

M_CAP

Benign

0.065

MetaRNN

Uncertain

0.74

D;D;D

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.4

L;.;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.88

PROVEAN

Uncertain

-3.5

D;D;D

REVEL

Uncertain

0.36

Sift

Uncertain

0.0020

D;D;T

Sift4G

Uncertain

0.016

D;D;D

Polyphen

1.0

D;.;D

Vest4

0.91

MutPred

0.65

Loss of disorder (P = 0.0632);.;.;

MVP

0.29

MPC

0.63

ClinPred

0.98

GERP RS

5.1

Varity_R

0.88

gMVP

0.86

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over