chr12-57796539-C-T

Position:

• chr12-57796539-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_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 (★★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000031 (0 hom.)
• Consequence: TSFM NM_005726.6 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 0.612

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.

• 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	Protein	UniProt
TSFM	NM_005726.6	c.934C>T	p.Arg312Trp	missense_variant	6/6	ENST00000652027.2	NP_005717.3
TSFM	NM_001172696.2	c.997C>T	p.Arg333Trp	missense_variant	7/7		NP_001166167.1
TSFM	NM_001172695.2	c.*342C>T		3_prime_UTR_variant	5/5		NP_001166166.1
TSFM	NM_001172697.2	c.571+3466C>T		intron_variant			NP_001166168.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSFM	ENST00000652027.2	c.934C>T	p.Arg312Trp	missense_variant	6/6		NM_005726.6	ENSP00000499171	P1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 151978 Hom.: 0 Cov.: 32

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: 41 AN: 1314842 Hom.: 0 Cov.: 31 AF XY: 0.0000375 AC XY: 24 AN XY: 639898

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: 5 AN: 151978 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74198

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.: 0

Bravo AF: 0.0000340

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.0000253 AC: 3

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

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	Baylor Genetics	Dec 07, 2023	- -
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	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 16, 2024	Variant summary: TSFM c.997C>T (p.Arg333Trp) results in a non-conservative amino acid change in the encoded protein sequence. Three of three in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.1e-05 in 1466820 control chromosomes (gnomAD database v4). c.997C>T has been reported in the literature in multiple individuals affected with Combined Oxidative Phosphorylation Deficiency 3 (e.g. Calvo_2012, Smeitink_2006). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in decreased protein level and reduction of assembled mitochondrial complexes I, IV and V (Smeitink_2006). The following publications have been ascertained in the context of this evaluation (PMID: 22277967, 17033963). ClinVar contains an entry for this variant (Variation ID: 5379). 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	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

Labcorp Genetics (formerly Invitae), Labcorp

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	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.67	D;.
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Pathogenic	0.81	D
MutationAssessor	Pathogenic	4.2	H;.
MutationTaster	Benign	1.0	A;A;A;A;A;A;A
PrimateAI	Uncertain	0.66	T
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	D
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

Other links and lift over

dbSNP: rs121909485; hg19: chr12-58190322;