rs387907238

Variant names:

• chr6-166366043-A-T
• rs387907238
• NM_016098.4:c.236T>A
• MPC1 p.Leu79His

Your query was ambiguous. Multiple possible variants found:

• chr6-166366043-A-T
• chr6-166366043-A-C

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

The NM_016098.4(MPC1):​c.236T>A​(p.Leu79His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: MPC1 NM_016098.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.68
• Publications: 12 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.

• 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
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.93
• PP5: Variant 6-166366043-A-T is Pathogenic according to our data. Variant chr6-166366043-A-T is described in ClinVar as Pathogenic. ClinVar VariationId is 35562.Status of the report is no_assertion_criteria_provided, 0 stars.

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.236T>A	p.Leu79His	missense	Exon 4 of 5	NP_057182.1	Q9Y5U8
	MPC1	NM_001270879.2		c.107T>A	p.Leu36His	missense	Exon 5 of 6	NP_001257808.1
	MPC1	NM_001376565.1		c.107T>A	p.Leu36His	missense	Exon 5 of 6	NP_001363494.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MPC1	ENST00000360961.11	TSL:5 MANE Select	c.236T>A	p.Leu79His	missense	Exon 4 of 5	ENSP00000354223.6	Q9Y5U8
	MPC1	ENST00000621630.1	TSL:5	c.236T>A	p.Leu79His	missense	Exon 4 of 5	ENSP00000479789.1	A0A087WVZ0
	MPC1	ENST00000922734.1		c.104T>A	p.Leu35His	missense	Exon 2 of 3	ENSP00000592793.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Mitochondrial pyruvate carrier deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.86	D
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.076	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Uncertain	0.36	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		8.7
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-7.0	D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.92
gMVP		0.93
Mutation Taster		=7/93	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

dbSNP: rs387907238;

hg19: chr6-166779531;