chr15-65003159-G-A

Variant names:

• chr15-65003159-G-A
• rs1054662962
• NM_139242.4:c.1073C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_139242.4(MTFMT):​c.1073C>T​(p.Ser358Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000186 in 1,613,528 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S358C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MTFMT NM_139242.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.76
• 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: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• Leigh syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Leigh syndrome with leukodystrophy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19307688).

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.1073C>T	p.Ser358Phe	missense	Exon 9 of 9	NP_640335.2	Q96DP5-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTFMT	ENST00000220058.9	TSL:1 MANE Select	c.1073C>T	p.Ser358Phe	missense	Exon 9 of 9	ENSP00000220058.4	Q96DP5-1
	MTFMT	ENST00000901062.1		c.1340C>T	p.Ser447Phe	missense	Exon 10 of 10	ENSP00000571121.1
	MTFMT	ENST00000901059.1		c.1226C>T	p.Ser409Phe	missense	Exon 9 of 9	ENSP00000571118.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152026 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000242

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461502 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727040

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 86224

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111756

Other (OTH) AF: 0.00 AC: 0 AN: 60360

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152026 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74244

African (AFR) AF: 0.0000242 AC: 1 AN: 41372

American (AMR) AF: 0.00 AC: 0 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10590

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2080

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.081	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.21	T
Eigen	Benign	0.012
Eigen_PC	Benign	0.052
FATHMM_MKL	Uncertain	0.77	D
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.82	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		4.8
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.11
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.023	D
Polyphen		0.61	P
Vest4		0.13
MutPred		0.34		Loss of disorder (P = 0.0089)
MVP		0.82
MPC		0.30
ClinPred		0.91	D
GERP RS		4.5
Varity_R		0.068
gMVP		0.31
Mutation Taster		=94/6	polymorphism

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: rs1054662962; hg19: chr15-65295497;