chr9-136410688-C-A

Position:

• chr9-136410688-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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. 13/20 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.610

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 16 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PMPCA	NM_015160.3	c.20C>A	p.Ala7Glu	missense_variant	1/13	ENST00000371717.8
PMPCA	XM_005266059.4	c.20C>A	p.Ala7Glu	missense_variant	1/12
PMPCA	NM_001282944.2	c.-279C>A		5_prime_UTR_variant	1/12
PMPCA	NM_001282946.2	c.-279C>A		5_prime_UTR_variant	1/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PMPCA	ENST00000371717.8	c.20C>A	p.Ala7Glu	missense_variant	1/13	1	NM_015160.3	P1

Frequencies

GnomAD3 genomes AF: 0.0126 AC: 1914 AN: 152186 Hom.: 16 Cov.: 33

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

GnomAD3 exomes AF: 0.0135 AC: 1632 AN: 121318 Hom.: 20 AF XY: 0.0133 AC XY: 915 AN XY: 68544

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 SAS exome AF: 0.00137

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.: 31 AF XY: 0.0132 AC XY: 8182 AN XY: 619766

Gnomad4 AFR exome AF: 0.00210

Gnomad4 AMR exome AF: 0.0103

Gnomad4 ASJ exome AF: 0.0127

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00193

Gnomad4 FIN exome AF: 0.0262

Gnomad4 NFE exome AF: 0.0144

Gnomad4 OTH exome AF: 0.0110

GnomAD4 genome AF: 0.0126 AC: 1913 AN: 152304 Hom.: 16 Cov.: 33 AF XY: 0.0137 AC XY: 1018 AN XY: 74474

Gnomad4 AFR AF: 0.00219

Gnomad4 AMR AF: 0.0179

Gnomad4 ASJ AF: 0.0101

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.0313

Gnomad4 NFE AF: 0.0167

Gnomad4 OTH AF: 0.0118

Alfa AF: 0.0135 Hom.: 16

Bravo AF: 0.0106

TwinsUK AF: 0.00728 AC: 27

ALSPAC AF: 0.0119 AC: 46

ESP6500AA AF: 0.00342 AC: 15

ESP6500EA AF: 0.0149 AC: 128

ExAC AF: 0.0115 AC: 1373

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	PMPCA: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	- -

PMPCA-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 08, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	11
DANN	Benign	0.65
DEOGEN2	Benign	0.10	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.040	N
LIST_S2	Benign	0.57	T
MetaRNN	Benign	0.0037	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.030
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.0080	D
Polyphen		0.074	B
Vest4		0.27
MPC		0.17
ClinPred		0.012	T
GERP RS		0.63
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Varity_R		0.12
gMVP		0.63

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

LitVar

Other links and lift over

dbSNP: rs149055087; hg19: chr9-139305140;