7-103311676-G-T

Variant names:

• chr7-103311676-G-T
• rs3087615
• NM_004279.3:c.1188G>T

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.1188G>T​(p.Glu396Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0852 in 1,613,374 control chromosomes in the GnomAD database, including 6,527 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.065 (395 hom., cov: 32)
  • Exomes 𝑓: 0.087 (6132 hom.)
• Consequence: PMPCB NM_004279.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.988
• Publications: 37 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, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018229485).
• BP6: Variant 7-103311676-G-T is Benign according to our data. Variant chr7-103311676-G-T is described in ClinVar as Benign. ClinVar VariationId is 1245557.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.121 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.1188G>T	p.Glu396Asp	missense	Exon 10 of 13	NP_004270.2
	PMPCB	NM_001438231.1		c.1188G>T	p.Glu396Asp	missense	Exon 10 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.1188G>T	p.Glu396Asp	missense	Exon 10 of 13	ENSP00000249269.4
	PMPCB	ENST00000428154.5	TSL:1	c.1188G>T	p.Glu396Asp	missense	Exon 10 of 12	ENSP00000390035.1
	PMPCB	ENST00000706454.1		c.1188G>T	p.Glu396Asp	missense	Exon 10 of 13	ENSP00000516392.1

Frequencies

GnomAD3 genomes AF: 0.0653 AC: 9928 AN: 152146 Hom.: 393 Cov.: 32

Gnomad AFR AF: 0.0243

Gnomad AMI AF: 0.0757

Gnomad AMR AF: 0.0946

Gnomad ASJ AF: 0.0631

Gnomad EAS AF: 0.0506

Gnomad SAS AF: 0.128

Gnomad FIN AF: 0.0627

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.0808

Gnomad OTH AF: 0.0602

GnomAD2 exomes AF: 0.0920 AC: 23105 AN: 251110 AF XY: 0.0930

Gnomad AFR exome AF: 0.0237

Gnomad AMR exome AF: 0.171

Gnomad ASJ exome AF: 0.0554

Gnomad EAS exome AF: 0.0437

Gnomad FIN exome AF: 0.0653

Gnomad NFE exome AF: 0.0801

Gnomad OTH exome AF: 0.0849

GnomAD4 exome AF: 0.0873 AC: 127605 AN: 1461110 Hom.: 6132 Cov.: 31 AF XY: 0.0885 AC XY: 64353 AN XY: 726880

African (AFR) AF: 0.0239 AC: 801 AN: 33478

American (AMR) AF: 0.159 AC: 7089 AN: 44652

Ashkenazi Jewish (ASJ) AF: 0.0569 AC: 1486 AN: 26128

East Asian (EAS) AF: 0.0591 AC: 2343 AN: 39678

South Asian (SAS) AF: 0.143 AC: 12288 AN: 86194

European-Finnish (FIN) AF: 0.0660 AC: 3527 AN: 53414

Middle Eastern (MID) AF: 0.0631 AC: 364 AN: 5766

European-Non Finnish (NFE) AF: 0.0851 AC: 94608 AN: 1111428

Other (OTH) AF: 0.0845 AC: 5099 AN: 60372

GnomAD4 genome AF: 0.0652 AC: 9932 AN: 152264 Hom.: 395 Cov.: 32 AF XY: 0.0658 AC XY: 4898 AN XY: 74454

African (AFR) AF: 0.0242 AC: 1005 AN: 41560

American (AMR) AF: 0.0945 AC: 1446 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0631 AC: 219 AN: 3468

East Asian (EAS) AF: 0.0501 AC: 260 AN: 5188

South Asian (SAS) AF: 0.130 AC: 625 AN: 4818

European-Finnish (FIN) AF: 0.0627 AC: 665 AN: 10598

Middle Eastern (MID) AF: 0.0578 AC: 17 AN: 294

European-Non Finnish (NFE) AF: 0.0809 AC: 5499 AN: 68014

Other (OTH) AF: 0.0601 AC: 127 AN: 2114

Alfa AF: 0.0754 Hom.: 1696

Bravo AF: 0.0665

TwinsUK AF: 0.0839 AC: 311

ALSPAC AF: 0.0820 AC: 316

ESP6500AA AF: 0.0245 AC: 108

ESP6500EA AF: 0.0835 AC: 718

ExAC AF: 0.0906 AC: 11000

Asia WGS AF: 0.100 AC: 347 AN: 3478

EpiCase AF: 0.0819

EpiControl AF: 0.0765

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	PMPCB-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	13
DANN	Uncertain	0.98
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.52
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.77	T
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		0.99
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.16
Sift	Benign	0.29	T
Sift4G	Benign	0.29	T
Polyphen		0.062	B
Vest4		0.53
MutPred		0.57		Loss of methylation at R401 (P = 0.1327)
MPC		0.18
ClinPred		0.050	T
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 (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: rs3087615; hg19: chr7-102952123; COSMIC: COSV50786108; COSMIC: COSV50786108;