rs587777688

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM2PP5_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

Scores

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 7.70

Publications

4 publications found

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 Gene-Disease associations (from GenCC):

fatal mitochondrial disease due to combined oxidative phosphorylation defect type 3
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
Leigh syndrome
Inheritance: AR Classification: MODERATE Submitted by: ClinGen

TSFM links:

ENSG00000257921 (HGNC:):

ENSG00000257921 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 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 VariationId is 155719.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005726.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TSFM	NM_005726.6	MANE Select	c.944G>A	p.Cys315Tyr	missense	Exon 6 of 6	NP_005717.3
TSFM	NM_001172696.2		c.1007G>A	p.Cys336Tyr	missense	Exon 7 of 7	NP_001166167.1
TSFM	NM_001172695.2		c.*352G>A		3_prime_UTR	Exon 5 of 5	NP_001166166.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TSFM	ENST00000652027.2	MANE Select	c.944G>A	p.Cys315Tyr	missense	Exon 6 of 6	ENSP00000499171.2
TSFM	ENST00000323833.12	TSL:1	c.1007G>A	p.Cys336Tyr	missense	Exon 7 of 7	ENSP00000313877.8
TSFM	ENST00000543727.5	TSL:1	c.571+3476G>A		intron	N/A	ENSP00000439342.1

Frequencies

GnomAD3 genomes

AF:

0.0000328

AC:

AN:

152224

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.00000600

AC:

AN:

166578

AF XY:

0.0000114

show subpopulations

Gnomad AFR exome

AF:

0.0000685

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000108

AC:

AN:

1300420

Hom.:

Cov.:

AF XY:

0.0000111

AC XY:

AN XY:

631626

show subpopulations

African (AFR)

AF:

0.0000340

AC:

AN:

29382

American (AMR)

AF:

0.00

AC:

AN:

26214

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18516

East Asian (EAS)

AF:

0.00

AC:

AN:

37532

South Asian (SAS)

AF:

0.00

AC:

AN:

54194

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5098

European-Non Finnish (NFE)

AF:

0.0000107

AC:

AN:

1029606

Other (OTH)

AF:

0.0000376

AC:

AN:

53254

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152224

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74364

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41470

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5202

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68038

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000267

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.00000849

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Fatal mitochondrial disease due to combined oxidative phosphorylation defect type 3

Pathogenic:3

May 31, 2021

Revvity Omics, Revvity

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Aug 23, 2023

Baylor Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Aug 19, 2014

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

not provided

Pathogenic:2

May 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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.

Sep 01, 2016

CeGaT Center for Human Genetics Tuebingen

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.74

BayesDel_addAF

Benign

-0.011

BayesDel_noAF

Uncertain

-0.070

CADD

Pathogenic

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.54

Eigen

Uncertain

0.46

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.85

M_CAP

Uncertain

0.22

MetaRNN

Uncertain

0.73

MetaSVM

Uncertain

0.026

MutationAssessor

Uncertain

2.7

PhyloP100

7.7

PrimateAI

Uncertain

0.74

PROVEAN

Pathogenic

-7.8

REVEL

Pathogenic

0.84

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0010

Polyphen

0.87

Vest4

0.72

MutPred

0.52

Gain of catalytic residue at F310 (P = 0.0037)

MVP

0.93

MPC

0.085

ClinPred

0.99

GERP RS

4.4

Varity_R

0.86

gMVP

0.66

Mutation Taster

=2/98

disease causing (ClinVar)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over