Genetic Variant PMPCA:c.*355A>G (chr9-136423619-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.51

Publications

17 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: 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	Effect	Exon rank	MANE	Protein	UniProt
PMPCA	NM_015160.3 link	c.*355A>G	3_prime_UTR_variant	Exon 13 of 13	ENST00000371717.8	NP_055975.1	Q10713-1
PMPCA	NM_001282946.2 link	c.*355A>G	3_prime_UTR_variant	Exon 13 of 13		NP_001269875.1	Q10713
PMPCA	NM_001282944.2 link	c.*355A>G	3_prime_UTR_variant	Exon 12 of 12		NP_001269873.1	Q10713-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PMPCA	ENST00000371717.8 link	c.*355A>G		3_prime_UTR_variant	Exon 13 of 13	1	NM_015160.3	ENSP00000360782.3		Q10713-1

Frequencies

GnomAD3 genomes

AF:

0.421

AC:

64001

AN:

151858

Hom.:

14128

Cov.:

show subpopulations

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.:

AF XY:

0.458

AC XY:

25622

AN XY:

55960

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.515

Heterozygous variant carriers

1235

2469

3704

4938

6173

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

290

580

870

1160

1450

<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:

0.422

AC:

64063

AN:

151976

Hom.:

14151

Cov.:

AF XY:

0.416

AC XY:

30918

AN XY:

74274

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

1893

3787

5680

7574

9467

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

596

1192

1788

2384

2980

<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:

0.472

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

(source)

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)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over