9-136418848-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2PM5PP5

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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A377T) has been classified as 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

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:1

Conservation

PhyloP100: 7.52

Publications

2 publications found

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 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

PMPCA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr9-136418847-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 221552.Status of the report is no_assertion_criteria_provided, 0 stars.

PP5

Variant 9-136418848-C-T is Pathogenic according to our data. Variant chr9-136418848-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 521567.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015160.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PMPCA	NM_015160.3	MANE Select	c.1130C>T	p.Ala377Val	missense	Exon 10 of 13	NP_055975.1
PMPCA	NM_001282946.2		c.830C>T	p.Ala277Val	missense	Exon 10 of 13	NP_001269875.1
PMPCA	NM_001282944.2		c.737C>T	p.Ala246Val	missense	Exon 9 of 12	NP_001269873.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PMPCA	ENST00000371717.8	TSL:1 MANE Select	c.1130C>T	p.Ala377Val	missense	Exon 10 of 13	ENSP00000360782.3
PMPCA	ENST00000444897.3	TSL:2	c.1130C>T	p.Ala377Val	missense	Exon 10 of 12	ENSP00000408393.2
PMPCA	ENST00000706376.1		c.1130C>T	p.Ala377Val	missense	Exon 10 of 14	ENSP00000516358.1

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

GnomAD2 exomes

AF:

0.00000798

AC:

AN:

250722

AF XY:

0.00000737

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 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

African (AFR)

AF:

0.00

AC:

AN:

33466

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52524

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5710

European-Non Finnish (NFE)

AF:

0.0000171

AC:

AN:

1111566

Other (OTH)

AF:

0.0000166

AC:

AN:

60358

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.449

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152294

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41564

American (AMR)

AF:

0.00

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5172

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68022

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:1

Apr 12, 2023

Genetic Services Laboratory, University of Chicago

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

DNA sequence analysis of the PMPCA gene demonstrated a sequence change, c.1130C>T, in exon 10 that results in an amino acid change, p.Ala377Val. The p.Ala377Val change affects a highly conserved amino acid residue located in a domain of the PMPCA protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Ala377Val substitution. This particular amino acid change does not appear to have been described in the literature in other individuals with PMPCA-related disorders, however, another laboratory has identified this variant in the homozygous state in an individual with global developmental delay, MRI findings of pontocerebellar hypoplasia, hypotonia, microcephaly, short stature, ataxia and autoimmune hepatitis (internal data). A different pathogenic sequence change affecting the same amino acid residue (c.1129G>A, p.Ala377Thr) has been described in the bi-allelic state in multiple individuals with PMPCA-related cerebellar ataxia (PMID: 27148589, 25808372). This sequence change has been described in the gnomAD database with a frequency of 0.001% in the overall population (dbSNP rs963172852). The p.Ala377Val amino acid change occurs in a region of the PMPCA gene where other missense sequence changes have been described in individuals with PMPCA-related disorders. These collective evidences indicate that this sequence change is likely pathogenic, however functional studies have not been performed to prove this conclusively.

Mar 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 377 of the PMPCA protein (p.Ala377Val). This variant is present in population databases (no rsID available, gnomAD 0.005%). This variant has not been reported in the literature in individuals affected with PMPCA-related conditions. ClinVar contains an entry for this variant (Variation ID: 521567). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PMPCA protein function with a negative predictive value of 80%. This variant disrupts the p.Ala377 amino acid residue in PMPCA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25808372, 27148589). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Inborn genetic diseases

Pathogenic:1

Apr 03, 2024

Ambry Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.88

BayesDel_addAF

Benign

0.010

BayesDel_noAF

Uncertain

-0.050

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.30

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.97

M_CAP

Benign

0.065

MetaRNN

Uncertain

0.74

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.4

PhyloP100

7.5

PrimateAI

Pathogenic

0.88

PROVEAN

Uncertain

-3.5

REVEL

Uncertain

0.36

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.016

Polyphen

1.0

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

Mutation Taster

=28/72

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over