rs587777419

Variant names:

• chr15-65029541-G-A
• rs587777419
• NM_139242.4:c.73C>T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_139242.4(MTFMT):​c.73C>T​(p.Gln25*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000022 in 1,363,614 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: MTFMT NM_139242.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 0.859
• Publications: 0 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: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 26 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-65029541-G-A is Pathogenic according to our data. Variant chr15-65029541-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 133325.Status of the report is criteria_provided_single_submitter, 1 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.73C>T	p.Gln25*	stop_gained	Exon 1 of 9	NP_640335.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTFMT	ENST00000220058.9	TSL:1 MANE Select	c.73C>T	p.Gln25*	stop_gained	Exon 1 of 9	ENSP00000220058.4
	MTFMT	ENST00000901062.1		c.73C>T	p.Gln25*	stop_gained	Exon 1 of 10	ENSP00000571121.1
	MTFMT	ENST00000901059.1		c.73C>T	p.Gln25*	stop_gained	Exon 1 of 9	ENSP00000571118.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 111566 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000220 AC: 3 AN: 1363614 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 671578

African (AFR) AF: 0.00 AC: 0 AN: 28114

American (AMR) AF: 0.00 AC: 0 AN: 32956

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24346

East Asian (EAS) AF: 0.00 AC: 0 AN: 32188

South Asian (SAS) AF: 0.00 AC: 0 AN: 76146

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4982

European-Non Finnish (NFE) AF: 0.00000282 AC: 3 AN: 1064978

Other (OTH) AF: 0.00 AC: 0 AN: 56500

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000331 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Combined oxidative phosphorylation defect type 15 (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Uncertain	-0.020
CADD	Pathogenic	35
DANN	Uncertain	0.99
Eigen	Benign	0.094
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.22	N
PhyloP100		0.86
Vest4		0.044
GERP RS		1.9
PromoterAI		-0.026	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=10/190	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs587777419; hg19: chr15-65321879;