chr12-57796461-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong

The NM_005726.6(TSFM):c.856C>T(p.Gln286*) variant causes a stop gained change. The variant allele was found at a frequency of 0.000688 in 1,596,460 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 Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.0013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00063 ( 0 hom. )

Consequence

TSFM
NM_005726.6 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 6.11

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 links:

ENSG00000257921 (HGNC:):

ENSG00000257921 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.125 CDS is truncated, and there are 1 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 12-57796461-C-T is Pathogenic according to our data. Variant chr12-57796461-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 155718.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSFM	NM_005726.6 link	c.856C>T	p.Gln286*	stop_gained	Exon 6 of 6	ENST00000652027.2	NP_005717.3	P43897-1E5KS95
TSFM	NM_001172696.2 link	c.919C>T	p.Gln307*	stop_gained	Exon 7 of 7		NP_001166167.1	P43897-2
TSFM	NM_001172695.2 link	c.*264C>T		3_prime_UTR_variant	Exon 5 of 5		NP_001166166.1	P43897-3
TSFM	NM_001172697.2 link	c.571+3388C>T		intron_variant	Intron 5 of 5		NP_001166168.1	P43897-4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSFM	ENST00000652027.2 link	c.856C>T	p.Gln286*	stop_gained	Exon 6 of 6		NM_005726.6	ENSP00000499171.2		P43897-1

Frequencies

GnomAD3 genomes

AF:

0.00125

AC:

191

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0145

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000514

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00154

AC:

358

AN:

232740

Hom.:

AF XY:

0.00148

AC XY:

186

AN XY:

125376

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000929

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0144

Gnomad NFE exome

AF:

0.000514

Gnomad OTH exome

AF:

0.00124

GnomAD4 exome

AF:

0.000628

AC:

907

AN:

1444252

Hom.:

Cov.:

AF XY:

0.000629

AC XY:

451

AN XY:

716628

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000938

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0125

Gnomad4 NFE exome

AF:

0.000194

Gnomad4 OTH exome

AF:

0.000503

GnomAD4 genome

AF:

0.00125

AC:

191

AN:

152208

Hom.:

Cov.:

AF XY:

0.00180

AC XY:

134

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0145

Gnomad4 NFE

AF:

0.000514

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000419

Hom.:

Bravo

AF:

0.000136

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00108

AC:

131

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Fatal mitochondrial disease due to combined oxidative phosphorylation defect type 3

Pathogenic:6

Mar 26, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 21, 2023

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with combined oxidative phosphorylation deficiency 3 (MIM#610505). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity (OMIM). (I) 0205 - Variant is predicted to result in a truncated protein (premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction) with less than 1/3 of the protein sequence affected. (SP) 0251 - This variant is heterozygous. (I) 0305 - Variant is present in gnomAD >=0.01 and <0.03 for a recessive condition (v2 & v3: 567 heterozygotes, 0 homozygotes). (I) 0704 - Another variant predicted to result in a truncated protein and located downstream to the one identified in this case has limited previous evidence for pathogenicity (DECIPHER). At least one protein truncating variant located downstream has been reported likely pathogenic by multiple diagnostic laboratories in ClinVar. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. The variant has been previously reported in patients with combined oxidative phosphorylation deficiency 3 (MIM#610505) (ClinVar; Cardiomyopathy database; PMIDs: 25037205, 29261183). (SP) 1001 - This variant has strong functional evidence supporting abnormal protein function. Molecular modeling predicted the coding-region mutations to cause protein instability, which was experimentally confirmed in cultured patient cells, with mitochondrial translation defect and lacking EFTs (PMID: 25037205). (SP) 1102 - Strong phenotype match for this individual. (SP) 1201 - Heterozygous variant detected in trans with a likely pathogenic heterozygous variant (NM_005726.5(TSFM):c.774G>C; p.(Gln258His)) in a recessive disease. (SP) 1206 - This variant has been shown to be paternally inherited (by segregation analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Aug 19, 2014

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jan 06, 2020

Reproductive Health Research and Development, BGI Genomics

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: curation

NM_001172696.1:c.919C>T in the TSFM gene has an allele frequency of 0.014 in European(Finnish) subpopulation in the gnomAD database.This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. It was detected in individual with autosomal recessive infantile-onset mitochondrial cardiomyopathy, compound heterozygous with c.944G>A (PMID: 25037205). Co-segregation evidence was observed in a pedigree, two patients were affected and one sibling unaffected (PMID: 25037205). Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP criteria applied: PVS1; PM3; PP1. -

Apr 19, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 08, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: TSFM c.919C>T (p.Gln307X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay. The variant allele was found at a frequency of 0.0015 in 232740 control chromosomes. Specifically, the variant has a high carrier frequency in the Finnish population (294/20428 Finnish alleles in gnomad). Despite the relatively high carrier frequency, the variant was not found in homozygous indivuals in Finnish control populations (including gnomad), suggesting that complete loss of TSFM might result in embryonic lethality or severe childhood diseases in humans (Lim_2014). c.919C>T has been reported in the compound heterozygous state in the literature in individuals affected with juvenile-onset Leigh disease, ataxia, neuropathy, and optic atrophy, including a family with two affected siblings in which the variant co-segregated with disease (Ahola_2014). Additionally, the variant was reported in the compound heterozygous state in a patient with Early-Onset Complex Chorea without Basal Ganglia Lesions (vanRiesen_2021). These data indicate that the variant is likely to be associated with disease. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Three submitters classified the variant as pathogenic/likely pathogenic while one classified as benign. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided

Pathogenic:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Gln307*) in the TSFM gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 40 amino acid(s) of the TSFM protein. This variant is present in population databases (rs201754030, gnomAD 1.4%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with clinical features of combined oxidative phosphorylation deficiency (PMID: 25037205, 33816677). It has also been observed to segregate with disease in related individuals. It is commonly reported in individuals of Finnish ancestry (PMID: 25078778). ClinVar contains an entry for this variant (Variation ID: 155718). This variant disrupts a region of the TSFM protein in which other variant(s) (p.Arg333Trp) have been determined to be pathogenic (PMID: 17033963, 20435138, 21741925, 22277967). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Sep 21, 2022

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense variant predicted to result in protein truncation, as the last 40 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; This variant is associated with the following publications: (PMID: 25078778, 25037205, 21228398, 31267352, 31589614, 34277617, 33816677) -

Jun 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Primary dilated cardiomyopathy

Pathogenic:1

Nov 26, 2014

Blueprint Genetics

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.65

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.95

FATHMM_MKL

Pathogenic

0.97

Vest4

0.39

GERP RS

5.4

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