dbSNP rs62000432: TSFM:p.Leu266Ile (chr12-57796401-C-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.796C>A(p.Leu266Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00122 in 1,602,486 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 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. L266H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0064 ( 12 hom., cov: 32)

Exomes 𝑓: 0.00068 ( 19 hom. )

Consequence

TSFM
NM_005726.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.922

Publications

3 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=0.005405307).

BP6

Variant 12-57796401-C-A is Benign according to our data. Variant chr12-57796401-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 235467.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 = 0.00643 (979/152332) while in subpopulation AFR AF = 0.0223 (928/41558). AF 95% confidence interval is 0.0211. There are 12 homozygotes in GnomAd4. There are 496 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 12 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.796C>A	p.Leu266Ile	missense	Exon 6 of 6	NP_005717.3
TSFM	NM_001172696.2		c.859C>A	p.Leu287Ile	missense	Exon 7 of 7	NP_001166167.1	P43897-2
TSFM	NM_001172695.2		c.*204C>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.796C>A	p.Leu266Ile	missense	Exon 6 of 6	ENSP00000499171.2	P43897-1
TSFM	ENST00000323833.12	TSL:1	c.859C>A	p.Leu287Ile	missense	Exon 7 of 7	ENSP00000313877.8	P43897-2
TSFM	ENST00000543727.5	TSL:1	c.571+3328C>A		intron	N/A	ENSP00000439342.1	P43897-4

Frequencies

GnomAD3 genomes

AF:

0.00639

AC:

972

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0222

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00235

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00478

GnomAD2 exomes

AF:

0.00186

AC:

427

AN:

229150

AF XY:

0.00138

show subpopulations

Gnomad AFR exome

AF:

0.0252

Gnomad AMR exome

AF:

0.00142

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000118

Gnomad OTH exome

AF:

0.00138

GnomAD4 exome

AF:

0.000676

AC:

981

AN:

1450154

Hom.:

Cov.:

AF XY:

0.000579

AC XY:

417

AN XY:

720300

show subpopulations

African (AFR)

AF:

0.0229

AC:

762

AN:

33290

American (AMR)

AF:

0.00144

AC:

AN:

42376

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25866

East Asian (EAS)

AF:

0.00

AC:

AN:

39314

South Asian (SAS)

AF:

0.000118

AC:

AN:

84520

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52712

Middle Eastern (MID)

AF:

0.00243

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.0000452

AC:

AN:

1106322

Other (OTH)

AF:

0.00140

AC:

AN:

60000

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

126

189

252

315

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.00643

AC:

979

AN:

152332

Hom.:

Cov.:

AF XY:

0.00666

AC XY:

496

AN XY:

74490

show subpopulations

African (AFR)

AF:

0.0223

AC:

928

AN:

41558

American (AMR)

AF:

0.00235

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.000207

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68034

Other (OTH)

AF:

0.00473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

100

151

201

251

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00261

Hom.:

Bravo

AF:

0.00713

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0220

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.00221

AC:

268

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Fatal mitochondrial disease due to combined oxidative phosphorylation defect type 3 (2)

not specified (1)

TSFM-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.36

CADD

Uncertain

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.079

Eigen

Benign

-0.014

Eigen_PC

Benign

0.14

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.81

MetaRNN

Benign

0.0054

MetaSVM

Benign

-0.77

MutationAssessor

Benign

1.5

PhyloP100

0.92

PrimateAI

Uncertain

0.48

PROVEAN

Benign

-0.48

REVEL

Benign

0.16

Sift

Benign

0.18

Sift4G

Benign

0.53

Polyphen

0.016

Vest4

0.28

MVP

0.83

MPC

0.30

ClinPred

0.012

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.087

gMVP

0.19

Mutation Taster

=99/1

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