15-65002962-CAAAAAAAAAAA-CAAAAAAAAAAAAA

Variant names:

• chr15-65002962-C-CAA
• rs398027674
• NM_139242.4:c.*98_*99dupTT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_139242.4(MTFMT):​c.*98_*99dupTT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.020 (70 hom., cov: 0)
  • Exomes 𝑓: 0.10 (1 hom.)
• Consequence: MTFMT NM_139242.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.893
• 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: Benign. The variant received -8 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0196 (1175/59880) while in subpopulation AFR AF = 0.0273 (388/14238). AF 95% confidence interval is 0.025. There are 70 homozygotes in GnomAd4. There are 515 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 70 AR gene

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.*98_*99dupTT		3_prime_UTR	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.*98_*99dupTT		3_prime_UTR	Exon 9 of 9	ENSP00000220058.4	Q96DP5-1
	MTFMT	ENST00000901062.1		c.*98_*99dupTT		3_prime_UTR	Exon 10 of 10	ENSP00000571121.1
	MTFMT	ENST00000901059.1		c.*98_*99dupTT		3_prime_UTR	Exon 9 of 9	ENSP00000571118.1

Frequencies

GnomAD3 genomes AF: 0.0196 AC: 1172 AN: 59898 Hom.: 70 Cov.: 0

Gnomad AFR AF: 0.0271

Gnomad AMI AF: 0.0665

Gnomad AMR AF: 0.0157

Gnomad ASJ AF: 0.0158

Gnomad EAS AF: 0.00329

Gnomad SAS AF: 0.00699

Gnomad FIN AF: 0.0287

Gnomad MID AF: 0.0192

Gnomad NFE AF: 0.0173

Gnomad OTH AF: 0.0266

GnomAD4 exome AF: 0.102 AC: 26531 AN: 259696 Hom.: 1 Cov.: 2 AF XY: 0.102 AC XY: 13449 AN XY: 131774

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

African (AFR) AF: 0.0600 AC: 387 AN: 6448

American (AMR) AF: 0.0812 AC: 467 AN: 5752

Ashkenazi Jewish (ASJ) AF: 0.103 AC: 564 AN: 5468

East Asian (EAS) AF: 0.0418 AC: 630 AN: 15078

South Asian (SAS) AF: 0.0831 AC: 829 AN: 9978

European-Finnish (FIN) AF: 0.113 AC: 1412 AN: 12470

Middle Eastern (MID) AF: 0.114 AC: 116 AN: 1022

European-Non Finnish (NFE) AF: 0.109 AC: 20862 AN: 190586

Other (OTH) AF: 0.0980 AC: 1264 AN: 12894

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0196 AC: 1175 AN: 59880 Hom.: 70 Cov.: 0 AF XY: 0.0190 AC XY: 515 AN XY: 27090

African (AFR) AF: 0.0273 AC: 388 AN: 14238

American (AMR) AF: 0.0157 AC: 78 AN: 4968

Ashkenazi Jewish (ASJ) AF: 0.0158 AC: 28 AN: 1772

East Asian (EAS) AF: 0.00331 AC: 6 AN: 1814

South Asian (SAS) AF: 0.00702 AC: 12 AN: 1710

European-Finnish (FIN) AF: 0.0287 AC: 43 AN: 1496

Middle Eastern (MID) AF: 0.0222 AC: 2 AN: 90

European-Non Finnish (NFE) AF: 0.0173 AC: 563 AN: 32512

Other (OTH) AF: 0.0265 AC: 20 AN: 754

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.89
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs398027674; hg19: chr15-65295300;