12-57782831-T-C

Variant names:

• chr12-57782831-T-C
• rs10747783
• NM_005726.6:c.30T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_005726.6(TSFM):​c.30T>C​(p.Phe10Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.338 in 1,594,138 control chromosomes in the GnomAD database, including 99,343 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (7160 hom., cov: 32)
  • Exomes 𝑓: 0.34 (92183 hom.)
• Consequence: TSFM NM_005726.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.116
• Publications: 46 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 12-57782831-T-C is Benign according to our data. Variant chr12-57782831-T-C is described in ClinVar as Benign. ClinVar VariationId is 310006.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.116 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.638 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSFM	NM_005726.6	MANE Select	c.30T>C	p.Phe10Phe	synonymous	Exon 1 of 6	NP_005717.3
	TSFM	NM_001172696.2		c.30T>C	p.Phe10Phe	synonymous	Exon 1 of 7	NP_001166167.1
	TSFM	NM_001172697.2		c.30T>C	p.Phe10Phe	synonymous	Exon 1 of 6	NP_001166168.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSFM	ENST00000652027.2	MANE Select	c.30T>C	p.Phe10Phe	synonymous	Exon 1 of 6	ENSP00000499171.2
	TSFM	ENST00000323833.12	TSL:1	c.30T>C	p.Phe10Phe	synonymous	Exon 1 of 7	ENSP00000313877.8
	TSFM	ENST00000543727.5	TSL:1	c.30T>C	p.Phe10Phe	synonymous	Exon 1 of 6	ENSP00000439342.1

Frequencies

GnomAD3 genomes AF: 0.277 AC: 42131 AN: 151962 Hom.: 7142 Cov.: 32

Gnomad AFR AF: 0.107

Gnomad AMI AF: 0.384

Gnomad AMR AF: 0.261

Gnomad ASJ AF: 0.286

Gnomad EAS AF: 0.656

Gnomad SAS AF: 0.566

Gnomad FIN AF: 0.379

Gnomad MID AF: 0.142

Gnomad NFE AF: 0.319

Gnomad OTH AF: 0.250

GnomAD2 exomes AF: 0.368 AC: 80952 AN: 220148 AF XY: 0.379

Gnomad AFR exome AF: 0.100

Gnomad AMR exome AF: 0.349

Gnomad ASJ exome AF: 0.278

Gnomad EAS exome AF: 0.635

Gnomad FIN exome AF: 0.363

Gnomad NFE exome AF: 0.324

Gnomad OTH exome AF: 0.316

GnomAD4 exome AF: 0.345 AC: 497089 AN: 1442058 Hom.: 92183 Cov.: 36 AF XY: 0.351 AC XY: 251101 AN XY: 715468

African (AFR) AF: 0.0971 AC: 3212 AN: 33086

American (AMR) AF: 0.337 AC: 14078 AN: 41836

Ashkenazi Jewish (ASJ) AF: 0.288 AC: 7424 AN: 25746

East Asian (EAS) AF: 0.703 AC: 27117 AN: 38592

South Asian (SAS) AF: 0.551 AC: 45868 AN: 83176

European-Finnish (FIN) AF: 0.357 AC: 18290 AN: 51230

Middle Eastern (MID) AF: 0.201 AC: 1151 AN: 5736

European-Non Finnish (NFE) AF: 0.326 AC: 360069 AN: 1103060

Other (OTH) AF: 0.334 AC: 19880 AN: 59596

GnomAD4 genome AF: 0.277 AC: 42185 AN: 152080 Hom.: 7160 Cov.: 32 AF XY: 0.286 AC XY: 21297 AN XY: 74338

African (AFR) AF: 0.108 AC: 4473 AN: 41522

American (AMR) AF: 0.262 AC: 3998 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.286 AC: 992 AN: 3468

East Asian (EAS) AF: 0.656 AC: 3389 AN: 5164

South Asian (SAS) AF: 0.567 AC: 2731 AN: 4820

European-Finnish (FIN) AF: 0.379 AC: 4002 AN: 10568

Middle Eastern (MID) AF: 0.150 AC: 44 AN: 294

European-Non Finnish (NFE) AF: 0.319 AC: 21666 AN: 67942

Other (OTH) AF: 0.256 AC: 541 AN: 2110

Alfa AF: 0.302 Hom.: 8389

Bravo AF: 0.257

Asia WGS AF: 0.593 AC: 2058 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 22, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Fatal mitochondrial disease due to combined oxidative phosphorylation defect type 3 Benign:3

Nov 19, 2019

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	8.4
DANN	Benign	0.68
PhyloP100		0.12
PromoterAI		0.093	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

dbSNP: rs10747783; hg19: chr12-58176614; COSMIC: COSV55744944; COSMIC: COSV55744944;