12-57782807-G-T

Variant names:

• chr12-57782807-G-T
• rs1190133492
• NM_005726.6:c.6G>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_005726.6(TSFM):​c.6G>T​(p.Ser2Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000139 in 1,439,194 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. S2S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TSFM NM_005726.6 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.07
• 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: Orphanet, Labcorp Genetics (formerly Invitae)
• Leigh syndrome

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen

ENSG00000257921 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP7: Synonymous conserved (PhyloP=1.07 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.6G>T	p.Ser2Ser	synonymous	Exon 1 of 6	NP_005717.3
	TSFM	NM_001172696.2		c.6G>T	p.Ser2Ser	synonymous	Exon 1 of 7	NP_001166167.1	P43897-2
	TSFM	NM_001172697.2		c.6G>T	p.Ser2Ser	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.6G>T	p.Ser2Ser	synonymous	Exon 1 of 6	ENSP00000499171.2	P43897-1
	TSFM	ENST00000323833.12	TSL:1	c.6G>T	p.Ser2Ser	synonymous	Exon 1 of 7	ENSP00000313877.8	P43897-2
	TSFM	ENST00000543727.5	TSL:1	c.6G>T	p.Ser2Ser	synonymous	Exon 1 of 6	ENSP00000439342.1	P43897-4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000139 AC: 2 AN: 1439194 Hom.: 0 Cov.: 30 AF XY: 0.00000280 AC XY: 2 AN XY: 713764

African (AFR) AF: 0.00 AC: 0 AN: 32998

American (AMR) AF: 0.00 AC: 0 AN: 41316

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25682

East Asian (EAS) AF: 0.00 AC: 0 AN: 38302

South Asian (SAS) AF: 0.00 AC: 0 AN: 82714

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51126

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5732

European-Non Finnish (NFE) AF: 0.00000182 AC: 2 AN: 1101828

Other (OTH) AF: 0.00 AC: 0 AN: 59496

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	8.0
DANN	Benign	0.71
PhyloP100		1.1
PromoterAI		-0.23	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6

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: rs1190133492; hg19: chr12-58176590;