12-57782802-A-T

Variant names:

• chr12-57782802-A-T
• rs768942138
• NM_005726.6:c.1A>T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_005726.6(TSFM):​c.1A>T​(p.Met1?) variant causes a initiator codon change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TSFM NM_005726.6 initiator_codon
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.79
• Publications: 1 publications found

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

ENSG00000257921 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 14 pathogenic variants. Next in-frame start position is after 51 codons. Genomic position: 57783203. Lost 0.154 part of the original CDS.
• 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	c.1A>T	p.Met1?	initiator_codon_variant	Exon 1 of 6	ENST00000652027.2	NP_005717.3
TSFM	NM_001172696.2	c.1A>T	p.Met1?	initiator_codon_variant	Exon 1 of 7		NP_001166167.1
TSFM	NM_001172697.2	c.1A>T	p.Met1?	initiator_codon_variant	Exon 1 of 6		NP_001166168.1
TSFM	NM_001172695.2	c.1A>T	p.Met1?	initiator_codon_variant	Exon 1 of 5		NP_001166166.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSFM	ENST00000652027.2	c.1A>T	p.Met1?	initiator_codon_variant	Exon 1 of 6		NM_005726.6	ENSP00000499171.2
ENSG00000257921	ENST00000546504.1	c.77-308A>T		intron_variant	Intron 1 of 3	2		ENSP00000449544.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1438084 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 713138

African (AFR) AF: 0.00 AC: 0 AN: 32990

American (AMR) AF: 0.00 AC: 0 AN: 41086

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25648

East Asian (EAS) AF: 0.00 AC: 0 AN: 38250

South Asian (SAS) AF: 0.00 AC: 0 AN: 82540

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51172

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5734

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1101192

Other (OTH) AF: 0.00 AC: 0 AN: 59472

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jul 06, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant has not been reported in the literature in individuals affected with TSFM-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the TSFM mRNA. The next in-frame methionine is located at codon 51. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Benign	22
DANN	Benign	0.94
DEOGEN2	Benign	0.11	T;.;.;.;T;.
Eigen	Benign	0.16
Eigen_PC	Benign	0.15
FATHMM_MKL	Benign	0.70	D
LIST_S2	Uncertain	0.90	D;D;D;D;D;D
M_CAP	Pathogenic	0.78	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D
MetaSVM	Benign	-0.32	T
PhyloP100		3.8
PROVEAN	Benign	-0.47	N;N;N;N;N;N
REVEL	Uncertain	0.47
Sift	Pathogenic	0.0	D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D
Polyphen		0.70	P;.;B;.;.;.
Vest4		0.89
MutPred		0.96		Gain of helix (P = 0.132);Gain of helix (P = 0.132);Gain of helix (P = 0.132);Gain of helix (P = 0.132);Gain of helix (P = 0.132);Gain of helix (P = 0.132);
MVP		0.54
ClinPred		1.0	D
GERP RS		4.7
PromoterAI		-0.34	Neutral
Varity_R		0.96
gMVP		0.63
Mutation Taster		=26/174	disease causing

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

Other links and lift over

dbSNP: rs768942138; hg19: chr12-58176585;