12-57782801-GAT-G

Variant names:

• chr12-57782801-GAT-G
• rs1486098900
• NM_005726.6:c.1_2delAT

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_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
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.79

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]

ENSG00000257921 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 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. Fraction of 0.999 CDS is truncated, and there are 3 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	c.1_2delAT	p.Met1fs	frameshift_variant, start_lost	Exon 1 of 6	ENST00000652027.2	NP_005717.3
TSFM	NM_001172696.2	c.1_2delAT	p.Met1fs	frameshift_variant, start_lost	Exon 1 of 7		NP_001166167.1
TSFM	NM_001172697.2	c.1_2delAT	p.Met1fs	frameshift_variant, start_lost	Exon 1 of 6		NP_001166168.1
TSFM	NM_001172695.2	c.1_2delAT	p.Met1fs	frameshift_variant, start_lost	Exon 1 of 5		NP_001166166.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSFM	ENST00000652027.2	c.1_2delAT	p.Met1fs	frameshift_variant, start_lost	Exon 1 of 6		NM_005726.6	ENSP00000499171.2
ENSG00000257921	ENST00000546504.1	c.77-308_77-307delAT		intron_variant	Intron 1 of 3	2		ENSP00000449544.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.96e-7 AC: 1 AN: 1437786 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 712962

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.08e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

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

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Computational scores

Source: dbNSFP v4.3

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

LitVar

Other links and lift over

dbSNP: rs1486098900; hg19: chr12-58176584;