rs62622397

Variant names:

• chr7-103298572-T-C
• rs62622397
• NM_004279.3:c.104T>C

Variant summary

Our verdict is Benign. The variant received -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. 15/21 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:3
• Conservation: PhyloP100: -0.0510
• Publications: 5 publications found

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: Illumina, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

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.104T>C	p.Leu35Ser	missense	Exon 2 of 13	NP_004270.2	O75439
	PMPCB	NM_001438231.1		c.104T>C	p.Leu35Ser	missense	Exon 2 of 12	NP_001425160.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PMPCB	ENST00000249269.9	TSL:1 MANE Select	c.104T>C	p.Leu35Ser	missense	Exon 2 of 13	ENSP00000249269.4	O75439
	PMPCB	ENST00000428154.5	TSL:1	c.104T>C	p.Leu35Ser	missense	Exon 2 of 12	ENSP00000390035.1	G3V0E4
	PMPCB	ENST00000706454.1		c.104T>C	p.Leu35Ser	missense	Exon 2 of 13	ENSP00000516392.1	A0A9L9PXI7

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

GnomAD2 exomes AF: 0.0200 AC: 5016 AN: 251238 AF XY: 0.0144

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 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

African (AFR) AF: 0.270 AC: 9035 AN: 33418

American (AMR) AF: 0.0167 AC: 745 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.000522 AC: 45 AN: 86148

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53396

Middle Eastern (MID) AF: 0.0125 AC: 72 AN: 5756

European-Non Finnish (NFE) AF: 0.000517 AC: 575 AN: 1111734

Other (OTH) AF: 0.0173 AC: 1044 AN: 60378

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

African (AFR) AF: 0.263 AC: 10887 AN: 41474

American (AMR) AF: 0.0257 AC: 394 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.00112 AC: 76 AN: 68032

Other (OTH) AF: 0.0596 AC: 126 AN: 2114

Alfa AF: 0.0543 Hom.: 1011

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.34	T
MetaRNN	Benign	0.0034	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	0.49	N
PhyloP100		-0.051
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.12	N
REVEL	Benign	0.019
Sift	Benign	0.18	T
Sift4G	Benign	0.25	T
Polyphen		0.0	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
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs62622397; hg19: chr7-102939019;