Genetic Variant TSFM:p.Met1fs (chr12-57782801-GAT-G) – ACMG Classification: Pathogenic (12 pts)

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_005726.6(TSFM):c.1_2delAT(p.Met1fs) variant causes a frameshift, start lost change. The variant allele was found at a frequency of 0.000000696 in 1,437,786 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

TSFM
NM_005726.6 frameshift, start_lost

Scores

Not classified

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 3.79

Publications

1 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: Pathogenic. The variant received 12 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 68 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 12-57782801-GAT-G is Pathogenic according to our data. Variant chr12-57782801-GAT-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3575052.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSFM	NM_005726.6 link	c.1_2delAT	p.Met1fs	frameshift_variant, start_lost	Exon 1 of 6	ENST00000652027.2	NP_005717.3	P43897-1E5KS95
TSFM	NM_001172696.2 link	c.1_2delAT	p.Met1fs	frameshift_variant, start_lost	Exon 1 of 7		NP_001166167.1	P43897-2
TSFM	NM_001172697.2 link	c.1_2delAT	p.Met1fs	frameshift_variant, start_lost	Exon 1 of 6		NP_001166168.1	P43897-4
TSFM	NM_001172695.2 link	c.1_2delAT	p.Met1fs	frameshift_variant, start_lost	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.1_2delAT	p.Met1fs	frameshift_variant, start_lost	Exon 1 of 6		NM_005726.6	ENSP00000499171.2		P43897-1
ENSG00000257921	ENST00000546504.1 link	c.77-308_77-307delAT		intron_variant	Intron 1 of 3	2		ENSP00000449544.1		H0YIJ7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.96e-7

AC:

AN:

1437786

Hom.:

AF XY:

0.00

AC XY:

AN XY:

712962

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32966

American (AMR)

AF:

0.00

AC:

AN:

41052

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25644

East Asian (EAS)

AF:

0.00

AC:

AN:

38220

South Asian (SAS)

AF:

0.00

AC:

AN:

82514

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51132

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5734

European-Non Finnish (NFE)

AF:

9.08e-7

AC:

AN:

1101064

Other (OTH)

AF:

0.00

AC:

AN:

59460

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Fatal mitochondrial disease due to combined oxidative phosphorylation defect type 3

Pathogenic:1

Apr 09, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

3.8

Mutation Taster

=36/164

disease causing

(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