15-65003103-T-G

Position:

chr15-65003103-T-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_139242.4(MTFMT):c.1129A>C(p.Lys377Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00173 in 1,610,146 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0011 ( 1 hom., cov: 31)

Exomes 𝑓: 0.0018 ( 1 hom. )

Consequence

MTFMT
NM_139242.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: 1.20

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0066463053).

BP6

Variant 15-65003103-T-G is Benign according to our data. Variant chr15-65003103-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 985377.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1, Benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MTFMT	NM_139242.4 link	c.1129A>C	p.Lys377Gln	missense_variant	9/9	ENST00000220058.9	NP_640335.2	Q96DP5-1
MTFMT	XM_005254158.6 link	c.1282A>C	p.Lys428Gln	missense_variant	9/9		XP_005254215.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
MTFMT	ENST00000220058.9 link	c.1129A>C	p.Lys377Gln	missense_variant	9/9	1	NM_139242.4	ENSP00000220058.4	Q96DP5-1
MTFMT	ENST00000558460.5 link	n.1129A>C		non_coding_transcript_exon_variant	9/10	5		ENSP00000452646.1	Q96DP5-1
MTFMT	ENST00000560717.5 link	n.*599A>C		non_coding_transcript_exon_variant	8/8	5		ENSP00000457257.1	H3BTN9
MTFMT	ENST00000560717.5 link	n.*599A>C		3_prime_UTR_variant	8/8	5		ENSP00000457257.1	H3BTN9

Frequencies

GnomAD3 genomes

AF:

0.00105

AC:

160

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000289

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000590

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00203

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000893

AC:

221

AN:

247374

Hom.:

AF XY:

0.000968

AC XY:

130

AN XY:

134230

show subpopulations

Gnomad AFR exome

AF:

0.000518

Gnomad AMR exome

AF:

0.000323

Gnomad ASJ exome

AF:

0.000100

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000166

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00172

Gnomad OTH exome

AF:

0.000500

GnomAD4 exome

AF:

0.00180

AC:

2623

AN:

1457850

Hom.:

Cov.:

AF XY:

0.00176

AC XY:

1274

AN XY:

724950

show subpopulations

Gnomad4 AFR exome

AF:

0.000360

Gnomad4 AMR exome

AF:

0.000384

Gnomad4 ASJ exome

AF:

0.0000384

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000105

Gnomad4 FIN exome

AF:

0.0000188

Gnomad4 NFE exome

AF:

0.00225

Gnomad4 OTH exome

AF:

0.00140

GnomAD4 genome

AF:

0.00105

AC:

160

AN:

152296

Hom.:

Cov.:

AF XY:

0.00109

AC XY:

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.000289

Gnomad4 AMR

AF:

0.000589

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00203

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00148

Hom.:

Bravo

AF:

0.00112

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00259

AC:

ESP6500AA

AF:

0.00109

AC:

ESP6500EA

AF:

0.00134

AC:

ExAC

AF:

0.000745

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 01, 2022	This sequence change replaces lysine, which is basic and polar, with glutamine, which is neutral and polar, at codon 377 of the MTFMT protein (p.Lys377Gln). This variant is present in population databases (rs34507711, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with MTFMT-related conditions. ClinVar contains an entry for this variant (Variation ID: 985377). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	MTFMT: BP4 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 22, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.54

CADD

Benign

DANN

Benign

0.87

DEOGEN2

Benign

0.15

Eigen

Benign

-0.77

Eigen_PC

Benign

-0.71

FATHMM_MKL

Benign

0.071

M_CAP

Benign

0.023

MetaRNN

Benign

0.0066

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.6

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.42

REVEL

Benign

0.058

Sift

Benign

0.56

Sift4G

Benign

0.14

Polyphen

0.017

Vest4

0.097

MVP

0.64

MPC

0.13

ClinPred

0.0037

GERP RS

0.90

Varity_R

0.063

gMVP

0.27

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over