rs121909485

Positions:

chr12-57796539-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_005726.6(TSFM):c.934C>T(p.Arg312Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000314 in 1,466,820 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R312L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000031 ( 0 hom. )

Consequence

TSFM
NM_005726.6 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 0.612

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.964

PP5

Variant 12-57796539-C-T is Pathogenic according to our data. Variant chr12-57796539-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 5379.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
TSFM	NM_005726.6 linkuse as main transcript	c.934C>T	p.Arg312Trp	missense_variant	6/6	ENST00000652027.2
TSFM	NM_001172696.2 linkuse as main transcript	c.997C>T	p.Arg333Trp	missense_variant	7/7
TSFM	NM_001172695.2 linkuse as main transcript	c.*342C>T		3_prime_UTR_variant	5/5
TSFM	NM_001172697.2 linkuse as main transcript	c.571+3466C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSFM	ENST00000652027.2 linkuse as main transcript	c.934C>T	p.Arg312Trp	missense_variant	6/6		NM_005726.6	P1	P43897-1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

151978

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

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:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000312

AC:

AN:

1314842

Hom.:

Cov.:

AF XY:

0.0000375

AC XY:

AN XY:

639898

show subpopulations

Gnomad4 AFR exome

AF:

0.000101

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000328

Gnomad4 OTH exome

AF:

0.0000371

GnomAD4 genome

AF:

0.0000329

AC:

AN:

151978

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74198

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00000882

Hom.:

Bravo

AF:

0.0000340

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000253

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Fatal mitochondrial disease due to combined oxidative phosphorylation defect type 3

Pathogenic:4

Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 2012	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 09, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 07, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jul 16, 2023	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 (COXPD3) (MIM#610505). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v3) <0.01 for a recessive condition (5 heterozygotes, 0 homozygotes). (SP) 0309 - Alternative amino acid changes at the same position have been observed in gnomAD (v2) (3 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. The variant has previously been reported as pathogenic in a homozygous state in more than five patients with COXPD3 (ClinVar, HGMD, PMID: 17033963, PMID: 31267352). (SP) 1001 - This variant has strong functional evidence supporting abnormal protein function. Functional studies in patient cells demonstrated decreased protein levels as well as a reduction in assembled mitochondrial complexes I, IV and V (PMID: 17033963). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 14, 2022

The c.997C>T (p.R333W) alteration is located in coding exon 7 of the TSFM gene. This alteration results from a C to T substitution at nucleotide position 997, causing the arginine (R) at amino acid position 333 to be replaced by a tryptophan (W). Based on data from the Genome Aggregation Database (gnomAD), the c.997C>T alteration was observed in 0.0015% (3/201,630) total alleles studied, with a frequency of 0.004% (1/23,492) in the African subpopulation. This alteration was reported homozygous in multiple unrelated patients with severe combined oxidative phosphorylation deficiency, born to consanguineous parents (Smeitink, 2006; Smits, 2011; Calvo, 2012; Shamseldin, 2012; Vedrenne, 2012). This amino acid position is highly conserved in available vertebrate species. The p.R333 amino acid is located in an evolutionarily conserved site in a subdomain of EFTs that interacts with EFTu. Molecular modeling predicted that the mutation disrupts local subdomain structure and the dimerization interface (Smeitink, 2006). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 21, 2024

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 333 of the TSFM protein (p.Arg333Trp). 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 missense change has been observed in individual(s) with mitochondrial disorders (PMID: 17033963, 21741925, 22277967). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Arg312Trp. ClinVar contains an entry for this variant (Variation ID: 5379). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TSFM protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects TSFM function (PMID: 20435138). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.67

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.35

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.67

D;.

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.96

D;D

M_CAP

Uncertain

0.24

MetaRNN

Pathogenic

0.96

D;D

MetaSVM

Pathogenic

0.81

MutationAssessor

Pathogenic

4.2

H;.

MutationTaster

Benign

1.0

A;A;A;A;A;A;A

PrimateAI

Uncertain

0.66

PROVEAN

Pathogenic

-7.0

D;D

REVEL

Pathogenic

0.90

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.88

MVP

0.93

MPC

0.32

ClinPred

1.0

GERP RS

2.4

Varity_R

0.82

gMVP

0.84

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