12-57782802-A-G

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1PM2PP5

The NM_005726.6(TSFM):c.1A>G(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.0000239 in 1,590,186 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000024 ( 0 hom. )

Consequence

TSFM
NM_005726.6 start_lost

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1

Conservation

PhyloP100: 3.79

Publications

1 publications found

Variant links:

Genes affected

TSFM (HGNC:12367): (Ts translation elongation factor, mitochondrial) This gene encodes a mitochondrial translation elongation factor. The encoded protein is an enzyme that catalyzes the exchange of guanine nucleotides on the translation elongation factor Tu during the elongation step of mitchondrial protein translation. Mutations in this gene are associated with combined oxidative phosphorylation deficiency-3 syndrome. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Mar 2010]

TSFM Gene-Disease associations (from GenCC):

fatal mitochondrial disease due to combined oxidative phosphorylation defect type 3
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
Leigh syndrome
Inheritance: AR Classification: MODERATE Submitted by: ClinGen

TSFM links:

ENSG00000257921 (HGNC:):

ENSG00000257921 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 11 ACMG points.

PVS1

Start lost variant, next in-frame start position is after 14 pathogenic variants. Next in-frame start position is after 51 codons. Genomic position: 57783203. Lost 0.154 part of the original CDS.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 12-57782802-A-G is Pathogenic according to our data. Variant chr12-57782802-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2061807.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSFM	NM_005726.6 link	c.1A>G	p.Met1?	start_lost	Exon 1 of 6	ENST00000652027.2	NP_005717.3	P43897-1E5KS95
TSFM	NM_001172696.2 link	c.1A>G	p.Met1?	start_lost	Exon 1 of 7		NP_001166167.1	P43897-2
TSFM	NM_001172697.2 link	c.1A>G	p.Met1?	start_lost	Exon 1 of 6		NP_001166168.1	P43897-4
TSFM	NM_001172695.2 link	c.1A>G	p.Met1?	start_lost	Exon 1 of 5		NP_001166166.1	P43897-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSFM	ENST00000652027.2 link	c.1A>G	p.Met1?	start_lost	Exon 1 of 6		NM_005726.6	ENSP00000499171.2		P43897-1
ENSG00000257921	ENST00000546504.1 link	c.77-308A>G		intron_variant	Intron 1 of 3	2		ENSP00000449544.1		H0YIJ7

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152102

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000937

AC:

AN:

213516

AF XY:

0.00000869

show subpopulations

Gnomad AFR exome

AF:

0.0000780

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000106

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000236

AC:

AN:

1438084

Hom.:

Cov.:

AF XY:

0.0000238

AC XY:

AN XY:

713138

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32990

American (AMR)

AF:

0.00

AC:

AN:

41086

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25648

East Asian (EAS)

AF:

0.00

AC:

AN:

38250

South Asian (SAS)

AF:

0.0000121

AC:

AN:

82540

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51172

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5734

European-Non Finnish (NFE)

AF:

0.0000291

AC:

AN:

1101192

Other (OTH)

AF:

0.0000168

AC:

AN:

59472

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.453

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152102

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74300

show subpopulations

African (AFR)

AF:

0.0000966

AC:

AN:

41414

American (AMR)

AF:

0.00

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68020

Other (OTH)

AF:

0.00

AC:

AN:

2084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000658

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.00000827

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:1

Feb 04, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change affects the initiator methionine of the TSFM mRNA. The next in-frame methionine is located at codon 51. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with TSFM-related conditions. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. -

Mar 06, 2024

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Observed with a second TSFM variant in a patient with features of a mitochondrial disease, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes (PMID: 32980267); Not observed at significant frequency in large population cohorts (gnomAD); Initiation codon variant in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 23174091, 32980267) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.44

BayesDel_noAF

Pathogenic

0.39

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.12

T;.;.;.;T;.

Eigen

Uncertain

0.25

Eigen_PC

Benign

0.22

FATHMM_MKL

Benign

0.70

LIST_S2

Uncertain

0.90

D;D;D;D;D;D

M_CAP

Pathogenic

0.71

MetaRNN

Pathogenic

0.99

D;D;D;D;D;D

MetaSVM

Uncertain

-0.25

PhyloP100

3.8

PROVEAN

Benign

-0.66

N;N;N;N;N;N

REVEL

Pathogenic

0.74

Sift

Pathogenic

0.0

D;D;D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D;D

Polyphen

0.92

P;.;B;.;.;.

Vest4

0.89

MutPred

0.97

Loss of disorder (P = 0.1109);Loss of disorder (P = 0.1109);Loss of disorder (P = 0.1109);Loss of disorder (P = 0.1109);Loss of disorder (P = 0.1109);Loss of disorder (P = 0.1109);

MVP

0.52

ClinPred

0.99

GERP RS

4.7

PromoterAI

-0.23

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.95

gMVP

0.72

Mutation Taster

=26/174

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

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12-57782802-A-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over