7-103297467-C-T

Variant names:

Variant summary

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

The NM_004279.3(PMPCB):c.8C>T(p.Ala3Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00301 in 1,543,624 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0022 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0031 ( 13 hom. )

Consequence

PMPCB
NM_004279.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 1.29

Publications

4 publications found

Variant links:

Genes affected

PMPCB (HGNC:9119): (peptidase, mitochondrial processing subunit beta) This gene is a member of the peptidase M16 family and encodes a protein with a zinc-binding motif. This protein is located in the mitochondrial matrix and catalyzes the cleavage of the leader peptides of precursor proteins newly imported into the mitochondria, though it only functions as part of a heterodimeric complex. [provided by RefSeq, Jul 2008]

PMPCB Gene-Disease associations (from GenCC):

multiple mitochondrial dysfunctions syndrome 6
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Illumina, Ambry Genetics

PMPCB 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=0.0047867).

BP6

Variant 7-103297467-C-T is Benign according to our data. Variant chr7-103297467-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 1335687.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00223 (339/152356) while in subpopulation NFE AF = 0.00417 (284/68042). AF 95% confidence interval is 0.00377. There are 0 homozygotes in GnomAd4. There are 163 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 13 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004279.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PMPCB	NM_004279.3	MANE Select	c.8C>T	p.Ala3Val	missense	Exon 1 of 13	NP_004270.2	O75439
	PMPCB	NM_001438231.1		c.8C>T	p.Ala3Val	missense	Exon 1 of 12	NP_001425160.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PMPCB	ENST00000249269.9	TSL:1 MANE Select	c.8C>T	p.Ala3Val	missense	Exon 1 of 13	ENSP00000249269.4	O75439
PMPCB	ENST00000428154.5	TSL:1	c.8C>T	p.Ala3Val	missense	Exon 1 of 12	ENSP00000390035.1	G3V0E4
PMPCB	ENST00000706454.1		c.8C>T	p.Ala3Val	missense	Exon 1 of 13	ENSP00000516392.1	A0A9L9PXI7

Frequencies

GnomAD3 genomes

AF:

0.00223

AC:

339

AN:

152238

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000603

Gnomad AMI

AF:

0.0154

Gnomad AMR

AF:

0.000523

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000828

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00417

Gnomad OTH

AF:

0.000955

GnomAD2 exomes

AF:

0.00201

AC:

392

AN:

195016

AF XY:

0.00214

show subpopulations

Gnomad AFR exome

AF:

0.000605

Gnomad AMR exome

AF:

0.000551

Gnomad ASJ exome

AF:

0.000603

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000447

Gnomad NFE exome

AF:

0.00369

Gnomad OTH exome

AF:

0.000886

GnomAD4 exome

AF:

0.00310

AC:

4309

AN:

1391268

Hom.:

Cov.:

AF XY:

0.00309

AC XY:

2112

AN XY:

684472

show subpopulations

African (AFR)

AF:

0.000610

AC:

AN:

31140

American (AMR)

AF:

0.000765

AC:

AN:

35292

Ashkenazi Jewish (ASJ)

AF:

0.000372

AC:

AN:

21482

East Asian (EAS)

AF:

0.0000259

AC:

AN:

38580

South Asian (SAS)

AF:

0.000963

AC:

AN:

75836

European-Finnish (FIN)

AF:

0.000532

AC:

AN:

50784

Middle Eastern (MID)

AF:

0.00117

AC:

AN:

4258

European-Non Finnish (NFE)

AF:

0.00374

AC:

4023

AN:

1076654

Other (OTH)

AF:

0.00220

AC:

126

AN:

57242

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

228

457

685

914

1142

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

148

296

444

592

740

<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:

0.00223

AC:

339

AN:

152356

Hom.:

Cov.:

AF XY:

0.00219

AC XY:

163

AN XY:

74502

show subpopulations

African (AFR)

AF:

0.000601

AC:

AN:

41570

American (AMR)

AF:

0.000523

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.000829

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.000188

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00417

AC:

284

AN:

68042

Other (OTH)

AF:

0.000945

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

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:

0.00320

Hom.:

Bravo

AF:

0.00219

TwinsUK

AF:

0.00431

AC:

ALSPAC

AF:

0.00493

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00326

AC:

ExAC

AF:

0.00208

AC:

251

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Inborn genetic diseases (1)

PMPCB-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.40

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.10

Eigen

Benign

-0.74

Eigen_PC

Benign

-0.67

FATHMM_MKL

Benign

0.045

LIST_S2

Benign

0.78

M_CAP

Benign

0.035

MetaRNN

Benign

0.0048

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

PhyloP100

1.3

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-0.65

REVEL

Benign

0.13

Sift

Benign

0.065

Sift4G

Benign

0.15

Polyphen

0.0

Vest4

0.35

MVP

0.22

MPC

0.13

ClinPred

0.056

GERP RS

2.2

PromoterAI

-0.22

Neutral

(source)

Varity_R

0.072

gMVP

0.49

Mutation Taster

=296/4

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