Genetic Variant NM_015160.3:c.20C>A (chr9-136410688-C-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_015160.3(PMPCA):c.20C>A(p.Ala7Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0133 in 1,414,204 control chromosomes in the GnomAD database, including 155 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A7T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.013 ( 16 hom., cov: 33)

Exomes 𝑓: 0.013 ( 139 hom. )

Consequence

PMPCA
NM_015160.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.610

Publications

7 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 links:

ENTR1 (HGNC:10667): (endosome associated trafficking regulator 1) Involved in several processes, including endocytic recycling; positive regulation of cilium assembly; and positive regulation of protein localization to cilium. Located in endosome; microtubule organizing center; and midbody. Colocalizes with retromer complex. [provided by Alliance of Genome Resources, Apr 2022]

ENTR1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0037292838).

BP6

Variant 9-136410688-C-A is Benign according to our data. Variant chr9-136410688-C-A is described in ClinVar as Benign. ClinVar VariationId is 1665005.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0126 (1913/152304) while in subpopulation AMR AF = 0.0179 (274/15304). AF 95% confidence interval is 0.0162. There are 16 homozygotes in GnomAd4. There are 1018 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 16 AR gene

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	UniProt
PMPCA	NM_015160.3	MANE Select	c.20C>A	p.Ala7Glu	missense	Exon 1 of 13	NP_055975.1	Q10713-1
PMPCA	NM_001282946.2		c.-279C>A		5_prime_UTR	Exon 1 of 13	NP_001269875.1
PMPCA	NM_001282944.2		c.-279C>A		5_prime_UTR	Exon 1 of 12	NP_001269873.1	Q10713-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PMPCA	ENST00000371717.8	TSL:1 MANE Select	c.20C>A	p.Ala7Glu	missense	Exon 1 of 13	ENSP00000360782.3	Q10713-1
PMPCA	ENST00000622209.4	TSL:1	n.29C>A		non_coding_transcript_exon	Exon 1 of 5
PMPCA	ENST00000444897.3	TSL:2	c.20C>A	p.Ala7Glu	missense	Exon 1 of 12	ENSP00000408393.2	Q5SXN9

Frequencies

GnomAD3 genomes

AF:

0.0126

AC:

1914

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00219

Gnomad AMI

AF:

0.00659

Gnomad AMR

AF:

0.0179

Gnomad ASJ

AF:

0.0101

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00165

Gnomad FIN

AF:

0.0313

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0167

Gnomad OTH

AF:

0.0120

GnomAD2 exomes

AF:

0.0135

AC:

1632

AN:

121318

AF XY:

0.0133

show subpopulations

Gnomad AFR exome

AF:

0.00221

Gnomad AMR exome

AF:

0.00778

Gnomad ASJ exome

AF:

0.0128

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0285

Gnomad NFE exome

AF:

0.0173

Gnomad OTH exome

AF:

0.0154

GnomAD4 exome

AF:

0.0134

AC:

16941

AN:

1261900

Hom.:

139

Cov.:

AF XY:

0.0132

AC XY:

8182

AN XY:

619766

show subpopulations

African (AFR)

AF:

0.00210

AC:

AN:

25658

American (AMR)

AF:

0.0103

AC:

184

AN:

17888

Ashkenazi Jewish (ASJ)

AF:

0.0127

AC:

249

AN:

19580

East Asian (EAS)

AF:

0.00

AC:

AN:

30922

South Asian (SAS)

AF:

0.00193

AC:

107

AN:

55570

European-Finnish (FIN)

AF:

0.0262

AC:

1021

AN:

38914

Middle Eastern (MID)

AF:

0.0197

AC:

AN:

5036

European-Non Finnish (NFE)

AF:

0.0144

AC:

14666

AN:

1017516

Other (OTH)

AF:

0.0110

AC:

561

AN:

50816

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

822

1644

2466

3288

4110

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

582

1164

1746

2328

2910

<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:

0.0126

AC:

1913

AN:

152304

Hom.:

Cov.:

AF XY:

0.0137

AC XY:

1018

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.00219

AC:

AN:

41590

American (AMR)

AF:

0.0179

AC:

274

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0101

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00166

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0313

AC:

332

AN:

10598

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0167

AC:

1138

AN:

68020

Other (OTH)

AF:

0.0118

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

102

204

305

407

509

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

<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:

0.0134

Hom.:

Bravo

AF:

0.0106

TwinsUK

AF:

0.00728

AC:

ALSPAC

AF:

0.0119

AC:

ESP6500AA

AF:

0.00342

AC:

ESP6500EA

AF:

0.0149

AC:

128

ExAC

AF:

0.0115

AC:

1373

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

PMPCA-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.62

CADD

Benign

(source)

DANN

Benign

0.65

DEOGEN2

Benign

0.10

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.040

LIST_S2

Benign

0.57

MetaRNN

Benign

0.0037

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

PhyloP100

-0.61

PrimateAI

Uncertain

0.72

PROVEAN

Benign

-1.2

REVEL

Benign

0.030

Sift

Uncertain

0.0060

Sift4G

Uncertain

0.0080

Polyphen

0.074

Vest4

0.27

MPC

0.17

ClinPred

0.012

GERP RS

0.63

PromoterAI

-0.020

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.1

Varity_R

0.12

gMVP

0.63

Mutation Taster

=99/1

polymorphism

(source)

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

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

Computational scores

Splicing

Publications

Other links and lift over