15-65003100-GCTT-G

Variant names:

• chr15-65003100-GCTT-G
• rs769122836
• NM_139242.4:c.1129_1131delAAG

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PM4_Supporting

The NM_139242.4(MTFMT):​c.1129_1131delAAG​(p.Lys377del) variant causes a conservative inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000344 in 1,600,622 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000040 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000034 (0 hom.)
• Consequence: MTFMT NM_139242.4 conservative_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 1.25

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_139242.4. Strenght limited to Supporting due to length of the change: 1aa.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTFMT	NM_139242.4	c.1129_1131delAAG	p.Lys377del	conservative_inframe_deletion	Exon 9 of 9	ENST00000220058.9	NP_640335.2
MTFMT	XM_005254158.6	c.1282_1284delAAG	p.Lys428del	conservative_inframe_deletion	Exon 9 of 9		XP_005254215.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTFMT	ENST00000220058.9	c.1129_1131delAAG	p.Lys377del	conservative_inframe_deletion	Exon 9 of 9	1	NM_139242.4	ENSP00000220058.4
MTFMT	ENST00000558460.5	n.1129_1131delAAG		non_coding_transcript_exon_variant	Exon 9 of 10	5		ENSP00000452646.1
MTFMT	ENST00000560717.5	n.*599_*601delAAG		non_coding_transcript_exon_variant	Exon 8 of 8	5		ENSP00000457257.1
MTFMT	ENST00000560717.5	n.*599_*601delAAG		3_prime_UTR_variant	Exon 8 of 8	5		ENSP00000457257.1

Frequencies

GnomAD3 genomes AF: 0.0000402 AC: 6 AN: 149384 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000670

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000782

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000490

GnomAD3 exomes AF: 0.0000164 AC: 4 AN: 243566 Hom.: 0 AF XY: 0.0000151 AC XY: 2 AN XY: 132266

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000170

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000900

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000338 AC: 49 AN: 1451124 Hom.: 0 AF XY: 0.0000319 AC XY: 23 AN XY: 721386

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000181

Gnomad4 OTH exome AF: 0.000702

GnomAD4 genome AF: 0.0000401 AC: 6 AN: 149498 Hom.: 0 Cov.: 31 AF XY: 0.0000413 AC XY: 3 AN XY: 72708

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000669

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000784

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000485

Bravo AF: 0.0000416

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Aug 11, 2021

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In-frame deletion of 1 amino acids in a non-repeat region; In silico analysis supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Jul 17, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.1129_1131del, results in the deletion of 1 amino acid(s) of the MTFMT protein (p.Lys377del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs769122836, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with MTFMT-related conditions. ClinVar contains an entry for this variant (Variation ID: 1031156). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Combined oxidative phosphorylation defect type 15 Uncertain:1

Apr 05, 2019

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

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

Sep 01, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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: rs769122836; hg19: chr15-65295438;