15-65003140-T-A

Variant names:

• chr15-65003140-T-A
• rs4586374
• NM_139242.4:c.1092A>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.1092A>T​(p.Gln364His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000821 in 1,461,358 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Synonymous variant affecting the same amino acid position (i.e. Q364Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: MTFMT NM_139242.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -6.06
• Publications: 4 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=0.07759851).

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.1092A>T	p.Gln364His	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.1092A>T	p.Gln364His	missense	Exon 9 of 9	ENSP00000220058.4	Q96DP5-1
	MTFMT	ENST00000901062.1		c.1359A>T	p.Gln453His	missense	Exon 10 of 10	ENSP00000571121.1
	MTFMT	ENST00000901059.1		c.1245A>T	p.Gln415His	missense	Exon 9 of 9	ENSP00000571118.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000402 AC: 1 AN: 248880 AF XY: 0.00000741

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000886

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461358 Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7 AN XY: 726946

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

American (AMR) AF: 0.00 AC: 0 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86144

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53386

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

European-Non Finnish (NFE) AF: 0.00000810 AC: 9 AN: 1111740

Other (OTH) AF: 0.0000497 AC: 3 AN: 60356

GnomAD4 genome Cov.: 31

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	0.0090
DANN	Benign	0.88
DEOGEN2	Benign	0.18	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.012	N
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.078	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L
PhyloP100		-6.1
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.13
Sift	Benign	0.076	T
Sift4G	Uncertain	0.040	D
Polyphen		0.0010	B
Vest4		0.077
MutPred		0.24		Loss of sheet (P = 0.0181)
MVP		0.32
MPC		0.11
ClinPred		0.054	T
GERP RS		-8.1
Varity_R		0.077
gMVP		0.42
Mutation Taster		=86/14	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: rs4586374; hg19: chr15-65295478;