Genetic Variant TSFM:p.Leu7Leu (chr12-57782820-C-T) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2BP4_StrongBP6_ModerateBP7

The NM_005726.6(TSFM):c.19C>T(p.Leu7Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000693 in 1,442,236 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. L7L) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

TSFM
NM_005726.6 synonymous

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.252

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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.77).

BP6

Variant 12-57782820-C-T is Benign according to our data. Variant chr12-57782820-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1653120.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=-0.252 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSFM	NM_005726.6 link	c.19C>T	p.Leu7Leu	synonymous_variant	Exon 1 of 6	ENST00000652027.2	NP_005717.3	P43897-1E5KS95
TSFM	NM_001172696.2 link	c.19C>T	p.Leu7Leu	synonymous_variant	Exon 1 of 7		NP_001166167.1	P43897-2
TSFM	NM_001172697.2 link	c.19C>T	p.Leu7Leu	synonymous_variant	Exon 1 of 6		NP_001166168.1	P43897-4
TSFM	NM_001172695.2 link	c.19C>T	p.Leu7Leu	synonymous_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.19C>T	p.Leu7Leu	synonymous_variant	Exon 1 of 6		NM_005726.6	ENSP00000499171.2		P43897-1
ENSG00000257921	ENST00000546504.1 link	c.77-290C>T		intron_variant	Intron 1 of 3	2		ENSP00000449544.1		H0YIJ7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.93e-7

AC:

AN:

1442236

Hom.:

Cov.:

AF XY:

0.00000140

AC XY:

AN XY:

715670

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33060

American (AMR)

AF:

0.00

AC:

AN:

41858

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25720

East Asian (EAS)

AF:

0.00

AC:

AN:

38490

South Asian (SAS)

AF:

0.00

AC:

AN:

83034

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51318

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5738

European-Non Finnish (NFE)

AF:

9.06e-7

AC:

AN:

1103414

Other (OTH)

AF:

0.00

AC:

AN:

59604

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Sep 29, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.77

CADD

Benign

4.4

(source)

DANN

Benign

0.89

PhyloP100

-0.25

PromoterAI

0.010

Neutral

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over