7-103298572-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004279.3(PMPCB):c.104T>C(p.Leu35Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0143 in 1,613,538 control chromosomes in the GnomAD database, including 2,697 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.075 (1439 hom., cov: 33)
  • Exomes 𝑓: 0.0079 (1258 hom.)
• Consequence: PMPCB NM_004279.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0510

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0033938587).
• BP6: Variant 7-103298572-T-C is Benign according to our data. Variant chr7-103298572-T-C is described in ClinVar as [Benign]. Clinvar id is 1268549.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.258 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PMPCB	NM_004279.3	c.104T>C	p.Leu35Ser	missense_variant	2/13	ENST00000249269.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PMPCB	ENST00000249269.9	c.104T>C	p.Leu35Ser	missense_variant	2/13	1	NM_004279.3	P1

Frequencies

GnomAD3 genomes AF: 0.0754 AC: 11467 AN: 152102 Hom.: 1436 Cov.: 33

Gnomad AFR AF: 0.263

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0258

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00112

Gnomad OTH AF: 0.0602

GnomAD3 exomes AF: 0.0200 AC: 5016 AN: 251238 Hom.: 590 AF XY: 0.0144 AC XY: 1951 AN XY: 135788

Gnomad AFR exome AF: 0.267

Gnomad AMR exome AF: 0.0145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000458

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000809

Gnomad OTH exome AF: 0.0116

GnomAD4 exome AF: 0.00788 AC: 11517 AN: 1461318 Hom.: 1258 Cov.: 30 AF XY: 0.00680 AC XY: 4946 AN XY: 726948

Gnomad4 AFR exome AF: 0.270

Gnomad4 AMR exome AF: 0.0167

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000522

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000517

Gnomad4 OTH exome AF: 0.0173

GnomAD4 genome AF: 0.0755 AC: 11490 AN: 152220 Hom.: 1439 Cov.: 33 AF XY: 0.0724 AC XY: 5392 AN XY: 74424

Gnomad4 AFR AF: 0.263

Gnomad4 AMR AF: 0.0257

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00112

Gnomad4 OTH AF: 0.0596

Alfa AF: 0.0324 Hom.: 328

Bravo AF: 0.0859

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.243 AC: 1071

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.0245 AC: 2972

Asia WGS AF: 0.0140 AC: 48 AN: 3478

EpiCase AF: 0.00109

EpiControl AF: 0.000889

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 26, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 05, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.73
Cadd	Benign	0.11
Dann	Benign	0.88
DEOGEN2	Benign	0.10	T;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.34	T;T
MetaRNN	Benign	0.0034	T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	0.49	N;.
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.12	N;N
REVEL	Benign	0.019
Sift	Benign	0.18	T;T
Sift4G	Benign	0.25	T;T
Polyphen		0.0	B;B
Vest4		0.045
MPC		0.18
ClinPred		0.00083	T
GERP RS		-1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.036
gMVP		0.43

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: rs62622397; hg19: chr7-102939019;