15-65021533-G-A

Variant names:

• chr15-65021533-G-A
• rs201431517
• NM_139242.4:c.626C>T
• MTFMT p.Ser209Leu

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PS3 PP3 PP5_Very_Strong

The NM_139242.4(MTFMT):​c.626C>T​(p.Ser209Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000697 in 1,610,362 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV002526406: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID:25911677, 28058511, 21907147)"" and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00057 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00071 (1 hom.)
• Consequence: MTFMT NM_139242.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:23
• Conservation: PhyloP100: 8.92
• Publications: 31 publications found

Genes affected

MTFMT (HGNC:29666): (mitochondrial methionyl-tRNA formyltransferase) The protein encoded by this nuclear gene localizes to the mitochondrion, where it catalyzes the formylation of methionyl-tRNA. [provided by RefSeq, Jun 2011]

MTFMT Gene-Disease associations (from GenCC):

• combined oxidative phosphorylation defect type 15

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• Leigh syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Leigh syndrome with leukodystrophy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV002526406: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 25911677, 28058511, 21907147)"; SCV000329428: Published functional studies demonstrate a damaging effect with reduced mitochondrial methionyl-tRNA formyltransferase protein activity (PMID: 25288793); SCV001421026: Studies have shown that this missense change results in skipping of exon 4, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 21907147, 25911677, 28058511).; SCV003802764: Functional studies demonstrated absence of MTFMT protein in patient fibroblasts, reduced levels of mitochondrially encoded polypeptides, and reduction in the assembly of complexes 1, IV and V. Additionally, patient fibroblasts exhibited severe defects in mitochondrial translation that could be rescued by exogenous expression of MTFMT (PMID: 21907147; PMID: 25911677; PMID: 30911575).; SCV003683497: Functional studies show that this variant causes exon skipping in patient fibroblasts, which results in reduced MTFMT activity (Tucker, 2011).; SCV005725670: The most pronounced variant effect results in significantly reduced complex 1 activity (e.g. Haack_2012). PMID: 22499348
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.803
• PP5: Variant 15-65021533-G-A is Pathogenic according to our data. Variant chr15-65021533-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 39827.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_139242.4. 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
	MTFMT	NM_139242.4	MANE Select	c.626C>T	p.Ser209Leu	missense	Exon 4 of 9	NP_640335.2	Q96DP5-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTFMT	ENST00000220058.9	TSL:1 MANE Select	c.626C>T	p.Ser209Leu	missense	Exon 4 of 9	ENSP00000220058.4	Q96DP5-1
	MTFMT	ENST00000901062.1		c.779C>T	p.Ser260Leu	missense	Exon 4 of 10	ENSP00000571121.1
	MTFMT	ENST00000901059.1		c.779C>T	p.Ser260Leu	missense	Exon 4 of 9	ENSP00000571118.1

Frequencies

GnomAD3 genomes AF: 0.000572 AC: 87 AN: 152224 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00106

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000349 AC: 87 AN: 249222 AF XY: 0.000311

Gnomad AFR exome AF: 0.000129

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000690

Gnomad OTH exome AF: 0.000496

GnomAD4 exome AF: 0.000710 AC: 1035 AN: 1458020 Hom.: 1 Cov.: 30 AF XY: 0.000692 AC XY: 502 AN XY: 725154

African (AFR) AF: 0.0000897 AC: 3 AN: 33456

American (AMR) AF: 0.000112 AC: 5 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26028

East Asian (EAS) AF: 0.00 AC: 0 AN: 39648

South Asian (SAS) AF: 0.00 AC: 0 AN: 85956

European-Finnish (FIN) AF: 0.0000376 AC: 2 AN: 53226

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 0.000897 AC: 995 AN: 1109046

Other (OTH) AF: 0.000498 AC: 30 AN: 60208

GnomAD4 genome AF: 0.000571 AC: 87 AN: 152342 Hom.: 0 Cov.: 32 AF XY: 0.000389 AC XY: 29 AN XY: 74516

African (AFR) AF: 0.000337 AC: 14 AN: 41582

American (AMR) AF: 0.00 AC: 0 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00106 AC: 72 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2108

Alfa AF: 0.000760 Hom.: 1

Bravo AF: 0.000468

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
8	-	-	not provided (8)
7	-	-	Combined oxidative phosphorylation defect type 15 (7)
1	-	-	Combined oxidative phosphorylation defect type 15;C4748826:Mitochondrial complex I deficiency, nuclear type 27 (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	Leigh syndrome (1)
1	-	-	Mitochondrial complex I deficiency, nuclear type 27 (1)
1	-	-	MTFMT-related disorder (1)
1	-	-	MTFMT-Related Disorders (1)
1	-	-	See cases (1)
1	-	-	Short stature;C0424503:Abnormal facial shape;C1848207:Poor speech;C1859200:Inability to walk by childhood/adolescence;C2677650:Decreased activity of mitochondrial complex I;C4021724:Cytochrome C oxidase-negative muscle fibers (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.13
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.61	D
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	1.0	D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.80	D
MetaSVM	Uncertain	0.0073	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		8.9
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-3.2	D
REVEL	Pathogenic	0.81
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.011	D
Varity_R		0.36
gMVP		0.83
Mutation Taster		=28/72	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs201431517; hg19: chr15-65313871;