rs201431517

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PP3PP5_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 (★★).

Frequency

Genomes: 𝑓 0.00057 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00071 ( 1 hom. )

Consequence

MTFMT
NM_139242.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:23

Conservation

PhyloP100: 8.92

Publications

31 publications found

Variant links:

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), G2P, Ambry Genetics
Leigh syndrome
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
Leigh syndrome with leukodystrophy
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

MTFMT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

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

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:

AN:

152224

Hom.:

Cov.:

show subpopulations

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:

AN:

249222

AF XY:

0.000311

show subpopulations

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.:

Cov.:

AF XY:

0.000692

AC XY:

502

AN XY:

725154

show subpopulations

African (AFR)

AF:

0.0000897

AC:

AN:

33456

American (AMR)

AF:

0.000112

AC:

AN:

44702

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26028

East Asian (EAS)

AF:

0.00

AC:

AN:

39648

South Asian (SAS)

AF:

0.00

AC:

AN:

85956

European-Finnish (FIN)

AF:

0.0000376

AC:

AN:

53226

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5750

European-Non Finnish (NFE)

AF:

0.000897

AC:

995

AN:

1109046

Other (OTH)

AF:

0.000498

AC:

AN:

60208

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

140

186

233

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

126

168

210

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000571

AC:

AN:

152342

Hom.:

Cov.:

AF XY:

0.000389

AC XY:

AN XY:

74516

show subpopulations

African (AFR)

AF:

0.000337

AC:

AN:

41582

American (AMR)

AF:

0.00

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00106

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000760

Hom.:

Bravo

AF:

0.000468

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00110

AC:

ExAC

AF:

0.000356

AC:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (8)

Combined oxidative phosphorylation defect type 15 (7)

Combined oxidative phosphorylation defect type 15;C4748826:Mitochondrial complex I deficiency, nuclear type 27 (1)

Inborn genetic diseases (1)

Leigh syndrome (1)

Mitochondrial complex I deficiency, nuclear type 27 (1)

MTFMT-related disorder (1)

MTFMT-Related Disorders (1)

See cases (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

BayesDel_noAF

Benign

-0.13

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.61

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Pathogenic

1.0

M_CAP

Uncertain

0.12

MetaRNN

Pathogenic

0.80

MetaSVM

Uncertain

0.0073

MutationAssessor

Uncertain

2.2

PhyloP100

8.9

PrimateAI

Uncertain

0.50

PROVEAN

Uncertain

-3.2

REVEL

Pathogenic

0.81

Sift

Uncertain

0.013

Sift4G

Uncertain

0.011

Polyphen

0.96

Vest4

0.80

MVP

0.94

MPC

0.45

ClinPred

0.59

GERP RS

5.5

Varity_R

0.36

gMVP

0.83

Mutation Taster

=28/72

disease causing (ClinVar)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over