chr6-166366005-G-C

Position:

• chr6-166366005-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_016098.4(MPC1):​c.274C>G​(p.Leu92Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: MPC1 NM_016098.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.36

Genes affected

MPC1 (HGNC:21606): (mitochondrial pyruvate carrier 1) The protein encoded by this gene is part of an MPC1/MPC2 heterodimer that is responsible for transporting pyruvate into mitochondria. The encoded protein is found in the inner mitochondrial membrane. Defects in this gene are a cause of mitochondrial pyruvate carrier deficiency. Several transcript variants, some protein coding and one non-protein coding, have been found for this gene. [provided by RefSeq, Aug 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM1: In a topological_domain Mitochondrial matrix (size 37) in uniprot entity MPC1_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_016098.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27237922).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MPC1	NM_016098.4	c.274C>G	p.Leu92Val	missense_variant	4/5	ENST00000360961.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MPC1	ENST00000360961.11	c.274C>G	p.Leu92Val	missense_variant	4/5	5	NM_016098.4	P3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Mitochondrial pyruvate carrier deficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

-

The missense variant p.L92V in MPC1 (NM_016098.4) has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.L92V variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. There is a small physicochemical difference between leucine and valine, which is not likely to impact secondary protein structure as these residues share similar properties. In silico tools are contradictory in their predictions and the residue is conserved across species. For these reasons, this variant has been classified as Uncertain Significance. In the absence of a second reportable variant/CNV the molecular diagnosis of MPC1- related disorder is not confirmed. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.48	T;D;D;T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.041
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.96	D;.;D;D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.27	T;T;T;T
MetaSVM	Benign	-0.78	T
MutationAssessor	Uncertain	2.8	M;.;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.2	N;.;.;.
REVEL	Uncertain	0.37
Sift	Benign	0.074	T;.;.;.
Sift4G	Benign	0.13	T;T;T;T
Polyphen		0.0040	B;.;.;.
Vest4		0.29
MutPred		0.55		Gain of MoRF binding (P = 0.1512);.;.;Gain of MoRF binding (P = 0.1512);
MVP		0.56
MPC		0.58
ClinPred		0.78	D
GERP RS		3.3
Varity_R		0.19
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-166779493;