15-65002962-CAAAAAAAAAAA-CAAAAAAAA

Variant names:

• chr15-65002962-CAAA-C
• rs398027674
• NM_139242.4:c.*97_*99delTTT

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BS1

The NM_139242.4(MTFMT):​c.*97_*99delTTT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0104 in 323,210 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0022 (0 hom., cov: 0)
  • Exomes 𝑓: 0.012 (0 hom.)
• Consequence: MTFMT NM_139242.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.153
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Variant has high frequency in the SAS (0.0167) population. However there is too low homozygotes in high coverage region: (expected more than 8, got 0).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00222 (135/60738) while in subpopulation AFR AF = 0.0087 (125/14376). AF 95% confidence interval is 0.00746. There are 0 homozygotes in GnomAd4. There are 66 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

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.*97_*99delTTT		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.*97_*99delTTT		3_prime_UTR	Exon 9 of 9	ENSP00000220058.4	Q96DP5-1
	MTFMT	ENST00000901062.1		c.*97_*99delTTT		3_prime_UTR	Exon 10 of 10	ENSP00000571121.1
	MTFMT	ENST00000901059.1		c.*97_*99delTTT		3_prime_UTR	Exon 9 of 9	ENSP00000571118.1

Frequencies

GnomAD3 genomes AF: 0.00222 AC: 135 AN: 60756 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00870

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00159

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: 0.0000302

Gnomad OTH AF: 0.00132

GnomAD4 exome AF: 0.0123 AC: 3237 AN: 262472 Hom.: 0 AF XY: 0.0126 AC XY: 1681 AN XY: 133234

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

African (AFR) AF: 0.0174 AC: 114 AN: 6546

American (AMR) AF: 0.0173 AC: 101 AN: 5824

Ashkenazi Jewish (ASJ) AF: 0.0126 AC: 70 AN: 5554

East Asian (EAS) AF: 0.0185 AC: 281 AN: 15166

South Asian (SAS) AF: 0.0189 AC: 190 AN: 10040

European-Finnish (FIN) AF: 0.0122 AC: 154 AN: 12622

Middle Eastern (MID) AF: 0.00963 AC: 10 AN: 1038

European-Non Finnish (NFE) AF: 0.0111 AC: 2138 AN: 192632

Other (OTH) AF: 0.0137 AC: 179 AN: 13050

⚠️ 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: 0.00222 AC: 135 AN: 60738 Hom.: 0 Cov.: 0 AF XY: 0.00240 AC XY: 66 AN XY: 27452

African (AFR) AF: 0.00870 AC: 125 AN: 14376

American (AMR) AF: 0.00159 AC: 8 AN: 5018

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1806

East Asian (EAS) AF: 0.00 AC: 0 AN: 1830

South Asian (SAS) AF: 0.00 AC: 0 AN: 1718

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1498

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 94

European-Non Finnish (NFE) AF: 0.0000302 AC: 1 AN: 33106

Other (OTH) AF: 0.00131 AC: 1 AN: 762

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.15
Mutation Taster		=100/0	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: rs398027674; hg19: chr15-65295300;