rs753611141

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PM5PP3PP5

The NM_015160.3(PMPCA):c.1129G>A(p.Ala377Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,612,604 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A377V) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

PMPCA
NM_015160.3 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:2

Conservation

PhyloP100: 9.50

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 Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: 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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.82

PP5

Variant 9-136418847-G-A is Pathogenic according to our data. Variant chr9-136418847-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 221552.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr9-136418847-G-A is described in UniProt as null. Variant chr9-136418847-G-A is described in UniProt as null. Variant chr9-136418847-G-A is described in UniProt as null.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PMPCA	NM_015160.3 linkuse as main transcript	c.1129G>A	p.Ala377Thr	missense_variant	10/13	ENST00000371717.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PMPCA	ENST00000371717.8 linkuse as main transcript	c.1129G>A	p.Ala377Thr	missense_variant	10/13	1	NM_015160.3	P1	Q10713-1

Frequencies

GnomAD3 genomes

AF:

0.0000395

AC:

AN:

152074

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000239

AC:

AN:

250696

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135594

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000173

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000753

AC:

AN:

1460530

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

726684

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000134

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000395

AC:

AN:

152074

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74288

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000393

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000227

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Hypertrophic cardiomyopathy;C0020258:Normal pressure hydrocephalus;C0029124:Optic atrophy;C0241816:Global brain atrophy;C0456909:Blindness;C1837397:Severe global developmental delay;C1839437:Chronic lactic acidosis;C1854699:Diffuse cerebellar atrophy;C1860834:Infantile muscular hypotonia;C1865916:Bilateral ptosis;C1865918:Restrictive external ophthalmoplegia;C2315100:Failure to thrive;C3203358:Hypoventilation

Pathogenic:1

Pathogenic, no assertion criteria provided

research

Gene Discovery Core-Manton Center, Boston Children's Hospital

Jan 22, 2016

- -

Autosomal recessive spinocerebellar ataxia 2

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 10, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.88

BayesDel_addAF

Benign

0.0035

BayesDel_noAF

Uncertain

0.040

Cadd

Pathogenic

Dann

Pathogenic

1.0

DEOGEN2

Benign

0.31

T;.;.

Eigen

Pathogenic

0.80

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

D;D;D

M_CAP

Benign

0.070

MetaRNN

Pathogenic

0.82

D;D;D

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.5

M;.;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.88

PROVEAN

Uncertain

-3.5

D;D;D

REVEL

Uncertain

0.46

Sift

Uncertain

0.0020

D;D;T

Sift4G

Uncertain

0.017

D;D;D

Polyphen

1.0

D;.;D

Vest4

0.98

MutPred

0.70

Gain of disorder (P = 0.0966);.;.;

MVP

0.35

MPC

0.63

ClinPred

0.96

GERP RS

5.1

Varity_R

0.76

gMVP

0.86

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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