rs587777418

Positions:

• chr15-65006127-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The NM_139242.4(MTFMT):​c.878G>A​(p.Ser293Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,278 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: MTFMT NM_139242.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: -0.203

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-65006127-C-T is Pathogenic according to our data. Variant chr15-65006127-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 133324.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.18451455). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MTFMT	NM_139242.4	c.878G>A	p.Ser293Asn	missense_variant	7/9	ENST00000220058.9	NP_640335.2
MTFMT	XM_005254158.6	c.1031G>A	p.Ser344Asn	missense_variant	7/9		XP_005254215.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MTFMT	ENST00000220058.9	c.878G>A	p.Ser293Asn	missense_variant	7/9	1	NM_139242.4	ENSP00000220058	P1
MTFMT	ENST00000558460.5	c.878G>A	p.Ser293Asn	missense_variant, NMD_transcript_variant	7/10	5		ENSP00000452646
MTFMT	ENST00000560717.5	c.*348G>A		3_prime_UTR_variant, NMD_transcript_variant	6/8	5		ENSP00000457257

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460278 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726440

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

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

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	1.3
DANN	Benign	0.59
DEOGEN2	Benign	0.15	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.012	N
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.33	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.35	N
REVEL	Uncertain	0.64
Sift	Benign	0.71	T
Sift4G	Benign	0.52	T
Polyphen		0.0010	B
Vest4		0.67
MutPred		0.38		Gain of sheet (P = 0.0827);
MVP		0.37
MPC		0.11
ClinPred		0.021	T
GERP RS		-1.2
Varity_R		0.052
gMVP		0.41

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs587777418; hg19: chr15-65298465;