Genetic Variant TSFM:p.Leu4Gln (chr12-57782812-T-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_005726.6(TSFM):c.11T>A(p.Leu4Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000694 in 1,440,064 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L4P) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

TSFM
NM_005726.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.17

Publications

0 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: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSFM	NM_005726.6 link	c.11T>A	p.Leu4Gln	missense_variant	Exon 1 of 6	ENST00000652027.2	NP_005717.3	P43897-1E5KS95
TSFM	NM_001172696.2 link	c.11T>A	p.Leu4Gln	missense_variant	Exon 1 of 7		NP_001166167.1	P43897-2
TSFM	NM_001172697.2 link	c.11T>A	p.Leu4Gln	missense_variant	Exon 1 of 6		NP_001166168.1	P43897-4
TSFM	NM_001172695.2 link	c.11T>A	p.Leu4Gln	missense_variant	Exon 1 of 5		NP_001166166.1	P43897-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSFM	ENST00000652027.2 link	c.11T>A	p.Leu4Gln	missense_variant	Exon 1 of 6		NM_005726.6	ENSP00000499171.2		P43897-1
ENSG00000257921	ENST00000546504.1 link	c.77-298T>A		intron_variant	Intron 1 of 3	2		ENSP00000449544.1		H0YIJ7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.94e-7

AC:

AN:

1440064

Hom.:

Cov.:

AF XY:

0.00000140

AC XY:

AN XY:

714346

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32998

American (AMR)

AF:

0.00

AC:

AN:

41458

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25692

East Asian (EAS)

AF:

0.00

AC:

AN:

38388

South Asian (SAS)

AF:

0.00

AC:

AN:

82802

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51172

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5736

European-Non Finnish (NFE)

AF:

9.07e-7

AC:

AN:

1102300

Other (OTH)

AF:

0.00

AC:

AN:

59518

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

-0.030

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.15

T;.;.;.;T;.

Eigen

Benign

-0.14

Eigen_PC

Benign

-0.26

FATHMM_MKL

Benign

0.096

LIST_S2

Benign

0.81

T;T;T;T;T;T

M_CAP

Benign

0.012

MetaRNN

Uncertain

0.47

T;T;T;T;T;T

MetaSVM

Benign

-0.79

MutationAssessor

Benign

1.8

L;L;L;.;.;L

PhyloP100

1.2

PrimateAI

Uncertain

0.48

PROVEAN

Benign

-1.1

N;N;N;N;N;N

REVEL

Benign

0.23

Sift

Uncertain

0.0040

D;D;D;D;D;D

Sift4G

Uncertain

0.0080

D;D;D;D;D;D

Polyphen

0.97

D;.;D;.;.;.

Vest4

0.52

MutPred

0.34

Gain of disorder (P = 0.0199);Gain of disorder (P = 0.0199);Gain of disorder (P = 0.0199);Gain of disorder (P = 0.0199);Gain of disorder (P = 0.0199);Gain of disorder (P = 0.0199);

MVP

0.73

MPC

0.23

ClinPred

0.89

GERP RS

4.7

PromoterAI

-0.11

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.36

gMVP

0.69

Mutation Taster

=86/14

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

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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over