7-103297487-T-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BS1_Supporting

The NM_004279.3(PMPCB):c.28T>G(p.Leu10Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000274 in 1,568,758 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00027 (0 hom.)
• Consequence: PMPCB NM_004279.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: -4.30

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]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.007922918).
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000282 (43/152236) while in subpopulation EAS AF= 0.00154 (8/5180). AF 95% confidence interval is 0.000768. There are 0 homozygotes in gnomad4. There are 21 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PMPCB	NM_004279.3	c.28T>G	p.Leu10Val	missense_variant	1/13	ENST00000249269.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PMPCB	ENST00000249269.9	c.28T>G	p.Leu10Val	missense_variant	1/13	1	NM_004279.3	P1

Frequencies

GnomAD3 genomes AF: 0.000283 AC: 43 AN: 152118 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000456

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000336 AC: 72 AN: 214108 Hom.: 0 AF XY: 0.000341 AC XY: 39 AN XY: 114494

Gnomad AFR exome AF: 0.000129

Gnomad AMR exome AF: 0.000199

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00192

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000527

Gnomad NFE exome AF: 0.000288

Gnomad OTH exome AF: 0.000390

GnomAD4 exome AF: 0.000273 AC: 387 AN: 1416522 Hom.: 0 Cov.: 31 AF XY: 0.000301 AC XY: 211 AN XY: 700032

Gnomad4 AFR exome AF: 0.0000931

Gnomad4 AMR exome AF: 0.000151

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00377

Gnomad4 SAS exome AF: 0.0000505

Gnomad4 FIN exome AF: 0.0000582

Gnomad4 NFE exome AF: 0.000194

Gnomad4 OTH exome AF: 0.000223

GnomAD4 genome AF: 0.000282 AC: 43 AN: 152236 Hom.: 0 Cov.: 33 AF XY: 0.000282 AC XY: 21 AN XY: 74442

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00154

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000456

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000483 Hom.: 1

Bravo AF: 0.000291

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000322 AC: 39

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Multiple mitochondrial dysfunctions syndrome 6 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 14, 2019	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Uncertain significance, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Aug 28, 2019	A heterozygous missense variant was identified, NM_004279.2(PMPCB):c.28T>G in exon 1 of 13 of the PMPCB gene. This substitution is predicted to create a minor amino acid change from leucine to valine at position 10 of the protein, NP_004270.2(PMPCB):p.(Leu10Val). The leucine at this position has low conservation (100 vertebrates, UCSC). It is located within the mitochondrial targeting sequence. In silico software predicts this variant to be benign (Polyphen, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD population database at a frequency of 0.03% (77 heterozygotes, 0 homozygotes). It has not been previously reported in clinical cases. Based on information available at the time of curation, this variant has been classified as a VARIANT of UNCERTAIN SIGNIFICANCE (VUS). -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 01, 2022

This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 10 of the PMPCB protein (p.Leu10Val). This variant is present in population databases (rs77305684, gnomAD 0.2%). This variant has not been reported in the literature in individuals affected with PMPCB-related conditions. ClinVar contains an entry for this variant (Variation ID: 1030758). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 30, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.59
Cadd	Benign	0.012
Dann	Benign	0.71
DEOGEN2	Benign	0.10	T;T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.0031	N
LIST_S2	Benign	0.72	T;T
M_CAP	Benign	0.0059	T
MetaRNN	Benign	0.0079	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	L;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.25	N;N
REVEL	Benign	0.053
Sift	Benign	0.20	T;T
Sift4G	Benign	0.20	T;T
Polyphen		0.0	B;B
Vest4		0.25
MVP		0.040
MPC		0.13
ClinPred		0.038	T
GERP RS		-9.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.056
gMVP		0.37

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: rs77305684; hg19: chr7-102937934;