6-166366042-AA-GT

Variant names:

• chr6-166366042-AA-GT
• NM_016098.4:c.236_237delTTinsAC
• MPC1 p.Leu79His

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PS1 PM1 PP3

The NM_016098.4(MPC1):​c.236_237delTTinsAC​(p.Leu79His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MPC1 NM_016098.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.68
• Publications: 0 publications found

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]

MPC1 Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• mitochondrial pyruvate carrier deficiency

  Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PS1: Transcript NM_016098.4 (MPC1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM1: In a chain Mitochondrial pyruvate carrier 1 (size 107) in uniprot entity MPC1_HUMAN there are 6 pathogenic changes around while only 2 benign (75%) in NM_016098.4
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016098.4. 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
	MPC1	NM_016098.4	MANE Select	c.236_237delTTinsAC	p.Leu79His	missense	N/A	NP_057182.1	Q9Y5U8
	MPC1	NM_001376569.1		c.186_187delTTinsAC	p.Ser63Pro	missense	N/A	NP_001363498.1
	MPC1	NM_001270879.2		c.107_108delTTinsAC	p.Leu36His	missense	N/A	NP_001257808.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MPC1	ENST00000360961.11	TSL:5 MANE Select	c.236_237delTTinsAC	p.Leu79His	missense	N/A	ENSP00000354223.6	Q9Y5U8
	MPC1	ENST00000621630.1	TSL:5	c.236_237delTTinsAC	p.Leu79His	missense	N/A	ENSP00000479789.1	A0A087WVZ0
	MPC1	ENST00000922734.1		c.104_105delTTinsAC	p.Leu35His	missense	N/A	ENSP00000592793.1

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.7

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr6-166779530;