chr6-166366059-G-T

Position:

• chr6-166366059-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_016098.4(MPC1):​c.220C>A​(p.Gln74Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: 9.31

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 4 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MPC1	NM_016098.4	c.220C>A	p.Gln74Lys	missense_variant	4/5	ENST00000360961.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MPC1	ENST00000360961.11	c.220C>A	p.Gln74Lys	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

Baylor Genetics

Jun 03, 2020

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.65	D;D;D;T
Eigen	Benign	0.089
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D;.;D;D
M_CAP	Benign	0.0065	T
MetaRNN	Uncertain	0.71	D;D;D;D
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	1.8	L;.;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-3.2	D;.;.;.
REVEL	Uncertain	0.41
Sift	Benign	0.046	D;.;.;.
Sift4G	Benign	0.15	T;T;T;T
Polyphen		0.095	B;.;.;.
Vest4		0.77
MutPred		0.50		Gain of methylation at Q74 (P = 0.0375);.;.;Gain of methylation at Q74 (P = 0.0375);
MVP		0.51
MPC		0.76
ClinPred		0.97	D
GERP RS		6.0
Varity_R		0.68
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs1779140481; hg19: chr6-166779547;