12-57782806-C-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_005726.6(TSFM):​c.5C>T​(p.Ser2Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00126 in 1,591,124 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S2S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0064 ( 11 hom., cov: 32)
Exomes 𝑓: 0.00072 ( 10 hom. )

Consequence

TSFM
NM_005726.6 missense

Scores

2
16

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.439

Publications

5 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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.00456059).
BP6
Variant 12-57782806-C-T is Benign according to our data. Variant chr12-57782806-C-T is described in ClinVar as [Benign]. Clinvar id is 703844.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00638 (971/152312) while in subpopulation AFR AF = 0.0226 (938/41572). AF 95% confidence interval is 0.0214. There are 11 homozygotes in GnomAd4. There are 469 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
BS2
High Homozygotes in GnomAd4 at 11 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TSFMNM_005726.6 linkc.5C>T p.Ser2Leu missense_variant Exon 1 of 6 ENST00000652027.2 NP_005717.3 P43897-1E5KS95
TSFMNM_001172696.2 linkc.5C>T p.Ser2Leu missense_variant Exon 1 of 7 NP_001166167.1 P43897-2
TSFMNM_001172697.2 linkc.5C>T p.Ser2Leu missense_variant Exon 1 of 6 NP_001166168.1 P43897-4
TSFMNM_001172695.2 linkc.5C>T p.Ser2Leu missense_variant Exon 1 of 5 NP_001166166.1 P43897-3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TSFMENST00000652027.2 linkc.5C>T p.Ser2Leu missense_variant Exon 1 of 6 NM_005726.6 ENSP00000499171.2 P43897-1
ENSG00000257921ENST00000546504.1 linkc.77-304C>T intron_variant Intron 1 of 3 2 ENSP00000449544.1 H0YIJ7

Frequencies

GnomAD3 genomes
AF:
0.00637
AC:
970
AN:
152194
Hom.:
11
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0226
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00164
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000588
Gnomad OTH
AF:
0.00144
GnomAD2 exomes
AF:
0.00158
AC:
339
AN:
214724
AF XY:
0.00115
show subpopulations
Gnomad AFR exome
AF:
0.0230
Gnomad AMR exome
AF:
0.00105
Gnomad ASJ exome
AF:
0.000215
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000420
Gnomad OTH exome
AF:
0.000554
GnomAD4 exome
AF:
0.000717
AC:
1032
AN:
1438812
Hom.:
10
Cov.:
30
AF XY:
0.000601
AC XY:
429
AN XY:
713520
show subpopulations
African (AFR)
AF:
0.0232
AC:
764
AN:
32994
American (AMR)
AF:
0.00119
AC:
49
AN:
41238
Ashkenazi Jewish (ASJ)
AF:
0.000156
AC:
4
AN:
25674
East Asian (EAS)
AF:
0.00
AC:
0
AN:
38272
South Asian (SAS)
AF:
0.000133
AC:
11
AN:
82626
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
51190
Middle Eastern (MID)
AF:
0.00105
AC:
6
AN:
5734
European-Non Finnish (NFE)
AF:
0.0000826
AC:
91
AN:
1101604
Other (OTH)
AF:
0.00180
AC:
107
AN:
59480
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.460
Heterozygous variant carriers
0
52
104
156
208
260
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
28
56
84
112
140
<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:
0.00638
AC:
971
AN:
152312
Hom.:
11
Cov.:
32
AF XY:
0.00630
AC XY:
469
AN XY:
74494
show subpopulations
African (AFR)
AF:
0.0226
AC:
938
AN:
41572
American (AMR)
AF:
0.00163
AC:
25
AN:
15298
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3466
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5184
South Asian (SAS)
AF:
0.000207
AC:
1
AN:
4834
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10620
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.0000588
AC:
4
AN:
68026
Other (OTH)
AF:
0.00142
AC:
3
AN:
2106
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.504
Heterozygous variant carriers
0
52
104
156
208
260
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
10
20
30
40
50
<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:
0.00183
Hom.:
3
Bravo
AF:
0.00778
ESP6500AA
AF:
0.0238
AC:
105
ESP6500EA
AF:
0.000117
AC:
1
ExAC
AF:
0.00176
AC:
213
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

Significance: Benign
Submissions summary: Benign:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:3
-
Breakthrough Genomics, Breakthrough Genomics
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:not provided

- -

Mar 03, 2015
GeneDx
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Feb 03, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Fatal mitochondrial disease due to combined oxidative phosphorylation defect type 3 Benign:2
Jan 02, 2020
Natera, Inc.
Significance:Benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Jan 12, 2018
Illumina Laboratory Services, Illumina
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.098
BayesDel_addAF
Benign
-0.52
T
BayesDel_noAF
Benign
-0.51
CADD
Benign
8.5
DANN
Benign
0.97
DEOGEN2
Benign
0.13
T;.;.;.;T;.
Eigen
Benign
-0.76
Eigen_PC
Benign
-0.67
FATHMM_MKL
Benign
0.16
N
LIST_S2
Uncertain
0.87
D;D;D;D;D;D
MetaRNN
Benign
0.0046
T;T;T;T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.20
N;N;N;.;.;N
PhyloP100
-0.44
PrimateAI
Benign
0.43
T
PROVEAN
Benign
-0.91
N;N;N;N;N;N
REVEL
Benign
0.057
Sift
Benign
0.18
T;T;T;T;T;T
Sift4G
Uncertain
0.022
D;D;D;D;D;D
Polyphen
0.0
B;.;B;.;.;.
Vest4
0.14
MVP
0.30
MPC
0.050
ClinPred
0.0098
T
GERP RS
2.2
PromoterAI
-0.25
Neutral
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.0
Varity_R
0.037
gMVP
0.56
Mutation Taster
=98/2
polymorphism

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

Other links and lift over

dbSNP: rs35957924; hg19: chr12-58176589; API