chr12-57782810-G-T

Variant names:

• chr12-57782810-G-T
• NM_005726.6:c.9G>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2 BP4_Strong BP6_Moderate BP7

The NM_005726.6(TSFM):​c.9G>T​(p.Leu3Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000417 in 1,439,044 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. L3L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000042 (0 hom.)
• Consequence: TSFM NM_005726.6 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0380
• Publications: 0 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):

• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• fatal mitochondrial disease due to combined oxidative phosphorylation defect type 3

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• Leigh syndrome

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen

ENSG00000257921 (HGNC:):

ACMG classification

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=-0.82).
• BP6: Variant 12-57782810-G-T is Benign according to our data. Variant chr12-57782810-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3000027.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.038 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005726.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSFM	NM_005726.6	MANE Select	c.9G>T	p.Leu3Leu	synonymous	Exon 1 of 6	NP_005717.3
	TSFM	NM_001172696.2		c.9G>T	p.Leu3Leu	synonymous	Exon 1 of 7	NP_001166167.1	P43897-2
	TSFM	NM_001172697.2		c.9G>T	p.Leu3Leu	synonymous	Exon 1 of 6	NP_001166168.1	P43897-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSFM	ENST00000652027.2	MANE Select	c.9G>T	p.Leu3Leu	synonymous	Exon 1 of 6	ENSP00000499171.2	P43897-1
	TSFM	ENST00000323833.12	TSL:1	c.9G>T	p.Leu3Leu	synonymous	Exon 1 of 7	ENSP00000313877.8	P43897-2
	TSFM	ENST00000543727.5	TSL:1	c.9G>T	p.Leu3Leu	synonymous	Exon 1 of 6	ENSP00000439342.1	P43897-4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000417 AC: 6 AN: 1439044 Hom.: 0 Cov.: 30 AF XY: 0.00000560 AC XY: 4 AN XY: 713754

African (AFR) AF: 0.00 AC: 0 AN: 32982

American (AMR) AF: 0.00 AC: 0 AN: 41310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25674

East Asian (EAS) AF: 0.00 AC: 0 AN: 38304

South Asian (SAS) AF: 0.00 AC: 0 AN: 82672

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51036

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5736

European-Non Finnish (NFE) AF: 0.00000545 AC: 6 AN: 1101852

Other (OTH) AF: 0.00 AC: 0 AN: 59478

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	3.8
DANN	Benign	0.73
PhyloP100		-0.038
PromoterAI		-0.048	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

hg19: chr12-58176593;