dbSNP rs114694283: TSFM:p.Val252Ile (chr12-57796359-G-A) – ACMG Classification: Benign (-20 pts)

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.754G>A(p.Val252Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00243 in 1,604,190 control chromosomes in the GnomAD database, including 77 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V252L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.013 ( 39 hom., cov: 32)

Exomes 𝑓: 0.0014 ( 38 hom. )

Consequence

TSFM
NM_005726.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.331

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):

mitochondrial disease
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0044727325).

BP6

Variant 12-57796359-G-A is Benign according to our data. Variant chr12-57796359-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 137761.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 = 0.0126 (1924/152334) while in subpopulation AFR AF = 0.0433 (1801/41578). AF 95% confidence interval is 0.0417. There are 39 homozygotes in GnomAd4. There are 919 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 39 AR gene

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	UniProt
TSFM	NM_005726.6	MANE Select	c.754G>A	p.Val252Ile	missense	Exon 6 of 6	NP_005717.3
TSFM	NM_001172696.2		c.817G>A	p.Val273Ile	missense	Exon 7 of 7	NP_001166167.1	P43897-2
TSFM	NM_001172695.2		c.*162G>A		3_prime_UTR	Exon 5 of 5	NP_001166166.1	P43897-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TSFM	ENST00000652027.2	MANE Select	c.754G>A	p.Val252Ile	missense	Exon 6 of 6	ENSP00000499171.2	P43897-1
TSFM	ENST00000323833.12	TSL:1	c.817G>A	p.Val273Ile	missense	Exon 7 of 7	ENSP00000313877.8	P43897-2
TSFM	ENST00000543727.5	TSL:1	c.571+3286G>A		intron	N/A	ENSP00000439342.1	P43897-4

Frequencies

GnomAD3 genomes

AF:

0.0126

AC:

1924

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0434

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00576

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:

0.000132

Gnomad OTH

AF:

0.0124

GnomAD2 exomes

AF:

0.00328

AC:

758

AN:

231108

AF XY:

0.00241

show subpopulations

Gnomad AFR exome

AF:

0.0469

Gnomad AMR exome

AF:

0.00197

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000591

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000107

Gnomad OTH exome

AF:

0.00223

GnomAD4 exome

AF:

0.00136

AC:

1978

AN:

1451856

Hom.:

Cov.:

AF XY:

0.00117

AC XY:

845

AN XY:

721300

show subpopulations

African (AFR)

AF:

0.0459

AC:

1530

AN:

33336

American (AMR)

AF:

0.00257

AC:

110

AN:

42774

Ashkenazi Jewish (ASJ)

AF:

0.0000774

AC:

AN:

25830

East Asian (EAS)

AF:

0.0000254

AC:

AN:

39414

South Asian (SAS)

AF:

0.0000944

AC:

AN:

84718

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52814

Middle Eastern (MID)

AF:

0.00191

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.000133

AC:

147

AN:

1107144

Other (OTH)

AF:

0.00281

AC:

169

AN:

60066

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

121

242

362

483

604

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

150

200

250

<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:

0.0126

AC:

1924

AN:

152334

Hom.:

Cov.:

AF XY:

0.0123

AC XY:

919

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.0433

AC:

1801

AN:

41578

American (AMR)

AF:

0.00575

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000132

AC:

AN:

68026

Other (OTH)

AF:

0.0123

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

197

295

394

492

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

<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:

0.00345

Hom.:

Bravo

AF:

0.0150

ESP6500AA

AF:

0.0409

AC:

180

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.00382

AC:

464

Asia WGS

AF:

0.00173

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Fatal mitochondrial disease due to combined oxidative phosphorylation defect type 3 (1)

not specified (1)

TSFM-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.61

CADD

Benign

0.24

(source)

DANN

Benign

0.84

DEOGEN2

Benign

0.092

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.070

LIST_S2

Benign

0.50

MetaRNN

Benign

0.0045

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.10

PhyloP100

-0.33

PrimateAI

Benign

0.27

PROVEAN

Benign

0.47

REVEL

Benign

0.14

Sift

Benign

0.57

Sift4G

Benign

0.57

Polyphen

0.0060

Vest4

0.10

MVP

0.40

MPC

0.047

ClinPred

0.00039

GERP RS

-1.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.010

gMVP

0.24

Mutation Taster

=100/0

polymorphism

(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

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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

Computational scores

Splicing

Publications

Other links and lift over