rs754222633

Positions:

• chr15-65003130-GAA-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The ENST00000220058.9(MTFMT):​c.1100_1101del​(p.Phe367SerfsTer22) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000131 in 152,094 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: 𝑓 0.000013 (0 hom., cov: 31)
• Consequence: MTFMT ENST00000220058.9 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 5.96

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0598 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-65003130-GAA-G is Pathogenic according to our data. Variant chr15-65003130-GAA-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 506018.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-65003130-GAA-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MTFMT	NM_139242.4	c.1100_1101del	p.Phe367SerfsTer22	frameshift_variant	9/9	ENST00000220058.9	NP_640335.2
MTFMT	XM_005254158.6	c.1253_1254del	p.Phe418SerfsTer22	frameshift_variant	9/9		XP_005254215.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MTFMT	ENST00000220058.9	c.1100_1101del	p.Phe367SerfsTer22	frameshift_variant	9/9	1	NM_139242.4	ENSP00000220058	P1
MTFMT	ENST00000558460.5	c.1100_1101del	p.Phe367SerfsTer22	frameshift_variant, NMD_transcript_variant	9/10	5		ENSP00000452646
MTFMT	ENST00000560717.5	c.*570_*571del		3_prime_UTR_variant, NMD_transcript_variant	8/8	5		ENSP00000457257

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152094 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000402 AC: 1 AN: 248660 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134914

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000887

Gnomad OTH exome AF: 0.00

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

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152094 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74278

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mitochondrial oxidative phosphorylation disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 25, 2017

The p.Phe367SerfsX22 (NM_139242.3 c.1100_1101delTT) variant in MTFMT has been pr eviously reported in 1 compound heterozygous individual with combined oxidative phosphorylation deficiency and mitochondrial disorders (Taylor 2014). This vari ant has been identified in (2/126,516) of European chromosomes by the Genome Agg regation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs754222633). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 367 and leads to a premature termination codon 22 amino a cids downstream. This alteration is then predicted to lead to a truncated or abs ent protein. Biallelic loss of function of the MTFMT gene has been associated wi th combined oxidative phosphorylation deficiency and mitochondrial disorders. In summary, the p.Phe367SerfsX22 variant is pathogenic for combined oxidative phos phorylation deficiency in an autosomal recessive manner based on a predicted var iant effect, biallelic occurrence in an individual with this disease and very lo w population frequency. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Apr 23, 2021

- -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs754222633; hg19: chr15-65295468;