rs587777417

Positions:

• chr15-65029460-AGAGCACCC-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_139242.4(MTFMT):​c.146_153delGGGTGCTC​(p.Arg49fs) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000507 in 1,379,580 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000051 (0 hom.)
• Consequence: MTFMT NM_139242.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 5.08

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-65029460-AGAGCACCC-A is Pathogenic according to our data. Variant chr15-65029460-AGAGCACCC-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 133323.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MTFMT	NM_139242.4	c.146_153delGGGTGCTC	p.Arg49fs	frameshift_variant	1/9	ENST00000220058.9	NP_640335.2
MTFMT	XM_005254158.6	c.146_153delGGGTGCTC	p.Arg49fs	frameshift_variant	1/9		XP_005254215.2
MTFMT	XR_001751081.2	n.172_179delGGGTGCTC		non_coding_transcript_exon_variant	1/5
MTFMT	XR_007064421.1	n.172_179delGGGTGCTC		non_coding_transcript_exon_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MTFMT	ENST00000220058.9	c.146_153delGGGTGCTC	p.Arg49fs	frameshift_variant	1/9	1	NM_139242.4	ENSP00000220058.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000825 AC: 1 AN: 121226 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 66662

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: 0.0000228

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000507 AC: 7 AN: 1379580 Hom.: 0 AF XY: 0.00000588 AC XY: 4 AN XY: 680530

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000652

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 19, 2024	PP1, PM2, PM3_supporting, PVS1 -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2017	- -

Combined oxidative phosphorylation defect type 15 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 01, 2014

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs587777417; hg19: chr15-65321798;