rs201754030

chr12-57796461-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_005726.6(TSFM):c.856C>T(p.Gln286Ter) 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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 6.11

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]

ACMG classification

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. There are 5 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/exons	MANE	UniProt
TSFM	NM_005726.6	c.856C>T	p.Gln286Ter	stop_gained	6/6	ENST00000652027.2
TSFM	NM_001172696.2	c.919C>T	p.Gln307Ter	stop_gained	7/7
TSFM	NM_001172695.2	c.*264C>T		3_prime_UTR_variant	5/5
TSFM	NM_001172697.2	c.571+3388C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSFM	ENST00000652027.2	c.856C>T	p.Gln286Ter	stop_gained	6/6		NM_005726.6	P1

Frequencies

GnomAD3 genomes AF: 0.00125 AC: 191 AN: 152208 Hom.: 0 Cov.: 32

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.: 0 AF XY: 0.00148 AC XY: 186 AN XY: 125376

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.: 0 Cov.: 31 AF XY: 0.000629 AC XY: 451 AN XY: 716628

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.: 0 Cov.: 32 AF XY: 0.00180 AC XY: 134 AN XY: 74356

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.: 0

Bravo AF: 0.000136

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00108 AC: 131

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fatal mitochondrial disease due to combined oxidative phosphorylation defect type 3 Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 08, 2022	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Oct 19, 2020	Based on the classification scheme VCGS_Germline_v1.3.3, 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) 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 (427 heterozygotes, 0 homozygotes). (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0704 - One downstream truncating variant comparable to the one identified in this case has limited previous evidence for pathogenicity (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, PMID: 25037205; 29261183). It has also been called once as benign in ClinVar without evidence. (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1001 - This variant has strong functional evidence supporting abnormal protein function. Additionally, 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 second pathogenic heterozygous variant (p.(Gln258His)) in a recessive disease. (SP) 1206 - This variant has been shown to be paternally inherited (segregation analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 19, 2014	- -
Pathogenic, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 10, 2023	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 21, 2022	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) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2019	- -

Primary dilated cardiomyopathy Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Blueprint Genetics

Nov 26, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.65
Cadd	Pathogenic	37
Dann	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	0.97	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
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

Other links and lift over

dbSNP: rs201754030; hg19: chr12-58190244;