rs199599204

chr15-65029598-G-Achr15-65029598-G-Cchr15-65029598-G-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM5 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_139242.4(MTFMT):c.16C>T(p.Arg6Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00925 in 1,429,500 control chromosomes in the GnomAD database, including 80 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R6P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0068 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0095 (76 hom.)
• Consequence: MTFMT NM_139242.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.40

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]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr15-65029597-C-G is described in Lovd as [Likely_pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.0064000785).
• BP6: Variant 15-65029598-G-A is Benign according to our data. Variant chr15-65029598-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 374493.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00676 (1028/151980) while in subpopulation NFE AF= 0.0107 (727/67894). AF 95% confidence interval is 0.0101. There are 4 homozygotes in gnomad4. There are 495 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTFMT	NM_139242.4	c.16C>T	p.Arg6Trp	missense_variant	1/9	ENST00000220058.9
MTFMT	XM_005254158.6	c.16C>T	p.Arg6Trp	missense_variant	1/9
MTFMT	XR_001751081.2	n.42C>T		non_coding_transcript_exon_variant	1/5
MTFMT	XR_007064421.1	n.42C>T		non_coding_transcript_exon_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTFMT	ENST00000220058.9	c.16C>T	p.Arg6Trp	missense_variant	1/9	1	NM_139242.4	P1

Frequencies

GnomAD3 genomes AF: 0.00678 AC: 1030 AN: 151870 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00186

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00295

Gnomad ASJ AF: 0.00721

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000623

Gnomad FIN AF: 0.0124

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.0107

Gnomad OTH AF: 0.00910

GnomAD3 exomes AF: 0.00718 AC: 517 AN: 72046 Hom.: 1 AF XY: 0.00696 AC XY: 290 AN XY: 41690

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00266

Gnomad ASJ exome AF: 0.00885

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000583

Gnomad FIN exome AF: 0.0110

Gnomad NFE exome AF: 0.0130

Gnomad OTH exome AF: 0.00583

GnomAD4 exome AF: 0.00955 AC: 12199 AN: 1277520 Hom.: 76 Cov.: 32 AF XY: 0.00915 AC XY: 5725 AN XY: 625926

Gnomad4 AFR exome AF: 0.00144

Gnomad4 AMR exome AF: 0.00298

Gnomad4 ASJ exome AF: 0.00776

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000329

Gnomad4 FIN exome AF: 0.0134

Gnomad4 NFE exome AF: 0.0109

Gnomad4 OTH exome AF: 0.00688

GnomAD4 genome AF: 0.00676 AC: 1028 AN: 151980 Hom.: 4 Cov.: 32 AF XY: 0.00666 AC XY: 495 AN XY: 74284

Gnomad4 AFR AF: 0.00185

Gnomad4 AMR AF: 0.00288

Gnomad4 ASJ AF: 0.00721

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000624

Gnomad4 FIN AF: 0.0124

Gnomad4 NFE AF: 0.0107

Gnomad4 OTH AF: 0.00900

Alfa AF: 0.00335 Hom.: 1

Bravo AF: 0.00617

ESP6500AA AF: 0.00233 AC: 5

ESP6500EA AF: 0.00914 AC: 48

ExAC AF: 0.00348 AC: 233

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Mar 20, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 09, 2016	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	MTFMT: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 12, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

MTFMT-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 04, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.26
Cadd	Benign	17
Dann	Uncertain	0.99
DEOGEN2	Benign	0.22	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.20	N
MetaRNN	Benign	0.0064	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.7	L
MutationTaster	Benign	1.0	N
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.25
Sift	Uncertain	0.0040	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.029	B
Vest4		0.15
MVP		0.54
MPC		0.31
ClinPred		0.049	T
GERP RS		0.48
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.040
gMVP		0.56

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

Publications

LitVar

Other links and lift over

dbSNP: rs199599204; hg19: chr15-65321936; COSMIC: COSV99075860; COSMIC: COSV99075860;