rs587777688

chr12-57796549-G-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

The NM_005726.6(TSFM):c.944G>A(p.Cys315Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 1,452,644 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: TSFM NM_005726.6 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 7.70

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 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-57796549-G-A is Pathogenic according to our data. Variant chr12-57796549-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 155719.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.944G>A	p.Cys315Tyr	missense_variant	6/6	ENST00000652027.2
TSFM	NM_001172696.2	c.1007G>A	p.Cys336Tyr	missense_variant	7/7
TSFM	NM_001172695.2	c.*352G>A		3_prime_UTR_variant	5/5
TSFM	NM_001172697.2	c.571+3476G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSFM	ENST00000652027.2	c.944G>A	p.Cys315Tyr	missense_variant	6/6		NM_005726.6	P1

Frequencies

GnomAD3 genomes AF: 0.0000328 AC: 5 AN: 152224 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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: 0.0000108 AC: 14 AN: 1300420 Hom.: 0 Cov.: 31 AF XY: 0.0000111 AC XY: 7 AN XY: 631626

Gnomad4 AFR exome AF: 0.0000340

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: 0.0000107

Gnomad4 OTH exome AF: 0.0000376

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152224 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74364

Gnomad4 AFR AF: 0.0000241

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: 0.0000712 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.00000849 AC: 1

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 31, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 19, 2014	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 23, 2023	- -

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 20, 2023	This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 336 of the TSFM protein (p.Cys336Tyr). This variant is present in population databases (rs587777688, gnomAD 0.004%). This missense change has been observed in individual(s) with clinical features of Leigh syndrome (PMID: 25037205). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as C315Y. ClinVar contains an entry for this variant (Variation ID: 155719). 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%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Benign	-0.011	T
BayesDel_noAF	Uncertain	-0.070
Cadd	Pathogenic	26
Dann	Uncertain	0.98
DEOGEN2	Uncertain	0.54	D;.
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.85	T;D
M_CAP	Uncertain	0.22	D
MetaRNN	Uncertain	0.73	D;D
MetaSVM	Uncertain	0.026	D
MutationAssessor	Uncertain	2.7	M;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-7.8	D;D
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		0.87	P;P
Vest4		0.72
MutPred		0.52		Gain of catalytic residue at F310 (P = 0.0037);.;
MVP		0.93
MPC		0.085
ClinPred		0.99	D
GERP RS		4.4
Varity_R		0.86
gMVP		0.66

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: rs587777688; hg19: chr12-58190332;