15-65029598-G-T

Variant names:

• chr15-65029598-G-T
• rs199599204
• NM_139242.4:c.16C>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_139242.4(MTFMT):​c.16C>A​(p.Arg6Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000157 in 1,277,546 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as (no stars). Synonymous variant affecting the same amino acid position (i.e. R6R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000016 (0 hom.)
• Consequence: MTFMT NM_139242.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.40
• Publications: 1 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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP7: Synonymous conserved (PhyloP=1.4 with no splicing effect.

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.16C>A	p.Arg6Arg	synonymous	Exon 1 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.16C>A	p.Arg6Arg	synonymous	Exon 1 of 9	ENSP00000220058.4	Q96DP5-1
	MTFMT	ENST00000901062.1		c.16C>A	p.Arg6Arg	synonymous	Exon 1 of 10	ENSP00000571121.1
	MTFMT	ENST00000901059.1		c.16C>A	p.Arg6Arg	synonymous	Exon 1 of 9	ENSP00000571118.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000157 AC: 2 AN: 1277546 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 625938

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 25706

American (AMR) AF: 0.00 AC: 0 AN: 24132

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21404

East Asian (EAS) AF: 0.0000375 AC: 1 AN: 26650

South Asian (SAS) AF: 0.00 AC: 0 AN: 69902

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4018

European-Non Finnish (NFE) AF: 9.81e-7 AC: 1 AN: 1019228

Other (OTH) AF: 0.00 AC: 0 AN: 51906

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0296732), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	5.8
DANN	Benign	0.71
PhyloP100		1.4
PromoterAI		-0.10	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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

Other links and lift over

dbSNP: rs199599204; hg19: chr15-65321936;