chr15-65002962-CAA-C

Variant names:

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

Variant summary

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

The NM_139242.4(MTFMT):​c.*98_*99delTT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0286 in 321,768 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 0.000049 (0 hom., cov: 0)
  • Exomes 𝑓: 0.035 (0 hom.)
• Consequence: MTFMT NM_139242.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.152
• 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 2 ACMG points.

• PM2: Variant has high frequency in the EAS (0.0572) population. However there is too low homozygotes in high coverage region: (expected more than 65, got 0).

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

Frequencies

GnomAD3 genomes AF: 0.0000494 AC: 3 AN: 60766 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0000696

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000199

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: 0.00

GnomAD4 exome AF: 0.0353 AC: 9204 AN: 261020 Hom.: 0 AF XY: 0.0356 AC XY: 4721 AN XY: 132578

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

African (AFR) AF: 0.0448 AC: 291 AN: 6496

American (AMR) AF: 0.0548 AC: 316 AN: 5762

Ashkenazi Jewish (ASJ) AF: 0.0380 AC: 210 AN: 5528

East Asian (EAS) AF: 0.0604 AC: 906 AN: 14996

South Asian (SAS) AF: 0.0436 AC: 436 AN: 9996

European-Finnish (FIN) AF: 0.0370 AC: 463 AN: 12526

Middle Eastern (MID) AF: 0.0307 AC: 32 AN: 1042

European-Non Finnish (NFE) AF: 0.0316 AC: 6051 AN: 191680

Other (OTH) AF: 0.0384 AC: 499 AN: 12994

⚠️ 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: 0.0000494 AC: 3 AN: 60748 Hom.: 0 Cov.: 0 AF XY: 0.0000728 AC XY: 2 AN XY: 27456

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

African (AFR) AF: 0.0000695 AC: 1 AN: 14386

American (AMR) AF: 0.000199 AC: 1 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: 0.00 AC: 0 AN: 762

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00000000000000965894), which strongly suggests a high chance of mosaicism in these individuals.

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;