Genetic Variant NM_004279.3:c.1188G>C (chr7-103311676-G-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004279.3(PMPCB):c.1188G>C(p.Glu396Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,642 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

PMPCB
NM_004279.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.988

Publications

37 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.12577888).

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.1188G>C	p.Glu396Asp	missense	Exon 10 of 13	NP_004270.2	O75439
	PMPCB	NM_001438231.1		c.1188G>C	p.Glu396Asp	missense	Exon 10 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.1188G>C	p.Glu396Asp	missense	Exon 10 of 13	ENSP00000249269.4	O75439
PMPCB	ENST00000428154.5	TSL:1	c.1188G>C	p.Glu396Asp	missense	Exon 10 of 12	ENSP00000390035.1	G3V0E4
PMPCB	ENST00000706454.1		c.1188G>C	p.Glu396Asp	missense	Exon 10 of 13	ENSP00000516392.1	A0A9L9PXI7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251110

AF XY:

0.00000737

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461642

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727120

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.0000224

AC:

AN:

44694

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39678

South Asian (SAS)

AF:

0.00

AC:

AN:

86232

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111854

Other (OTH)

AF:

0.00

AC:

AN:

60392

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.400

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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.54

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.49

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.14

Eigen

Benign

-0.57

Eigen_PC

Benign

-0.52

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.77

M_CAP

Benign

0.0087

MetaRNN

Benign

0.13

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.2

PhyloP100

0.99

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-2.1

REVEL

Benign

0.18

Sift

Benign

0.29

Sift4G

Benign

0.29

Polyphen

0.062

Vest4

0.53

MutPred

0.57

Loss of methylation at R401 (P = 0.1327)

MVP

0.15

MPC

0.18

ClinPred

0.40

GERP RS

0.80

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.17

gMVP

0.87

Mutation Taster

=97/3

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over