7-103297467-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

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. 12/21 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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.29

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 -16 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 [Likely_benign]. Clinvar id 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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PMPCB	NM_004279.3	c.8C>T	p.Ala3Val	missense_variant	1/13	ENST00000249269.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PMPCB	ENST00000249269.9	c.8C>T	p.Ala3Val	missense_variant	1/13	1	NM_004279.3	P1

Frequencies

GnomAD3 genomes AF: 0.00223 AC: 339 AN: 152238 Hom.: 0 Cov.: 33

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

GnomAD3 exomes AF: 0.00201 AC: 392 AN: 195016 Hom.: 1 AF XY: 0.00214 AC XY: 223 AN XY: 104238

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 SAS exome AF: 0.000812

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.: 13 Cov.: 31 AF XY: 0.00309 AC XY: 2112 AN XY: 684472

Gnomad4 AFR exome AF: 0.000610

Gnomad4 AMR exome AF: 0.000765

Gnomad4 ASJ exome AF: 0.000372

Gnomad4 EAS exome AF: 0.0000259

Gnomad4 SAS exome AF: 0.000963

Gnomad4 FIN exome AF: 0.000532

Gnomad4 NFE exome AF: 0.00374

Gnomad4 OTH exome AF: 0.00220

GnomAD4 genome AF: 0.00223 AC: 339 AN: 152356 Hom.: 0 Cov.: 33 AF XY: 0.00219 AC XY: 163 AN XY: 74502

Gnomad4 AFR AF: 0.000601

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00417

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.00350 Hom.: 1

Bravo AF: 0.00219

TwinsUK AF: 0.00431 AC: 16

ALSPAC AF: 0.00493 AC: 19

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00326 AC: 28

ExAC AF: 0.00208 AC: 251

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 17, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2021	- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 08, 2022

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. -

PMPCB-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 09, 2023

This variant is classified as likely 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	Uncertain	0.40
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.38
Cadd	Benign	17
Dann	Uncertain	0.99
DEOGEN2	Benign	0.10	T;T
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.045	N
LIST_S2	Benign	0.78	T;T
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.0048	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.65	N;N
REVEL	Benign	0.13
Sift	Benign	0.065	T;D
Sift4G	Benign	0.15	T;T
Polyphen		0.0	B;B
Vest4		0.35
MVP		0.22
MPC		0.13
ClinPred		0.056	T
GERP RS		2.2
Varity_R		0.072
gMVP		0.49

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: rs138251541; hg19: chr7-102937914; COSMIC: COSV99031110;