12-57782831-T-C

Position:

• chr12-57782831-T-C

Variant summary

Our verdict is Benign. Variant got -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

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 Benign. Variant got -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 id is 310006.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-57782831-T-C is described in Lovd as [Benign].
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSFM	NM_005726.6	c.30T>C	p.Phe10Phe	synonymous_variant	1/6	ENST00000652027.2	NP_005717.3
TSFM	NM_001172696.2	c.30T>C	p.Phe10Phe	synonymous_variant	1/7		NP_001166167.1
TSFM	NM_001172697.2	c.30T>C	p.Phe10Phe	synonymous_variant	1/6		NP_001166168.1
TSFM	NM_001172695.2	c.30T>C	p.Phe10Phe	synonymous_variant	1/5		NP_001166166.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSFM	ENST00000652027.2	c.30T>C	p.Phe10Phe	synonymous_variant	1/6		NM_005726.6	ENSP00000499171.2
ENSG00000257921	ENST00000546504.1	c.77-279T>C		intron_variant		2		ENSP00000449544.1

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

GnomAD3 exomes AF: 0.368 AC: 80952 AN: 220148 Hom.: 16739 AF XY: 0.379 AC XY: 44994 AN XY: 118842

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 SAS exome AF: 0.562

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

Gnomad4 AFR exome AF: 0.0971

Gnomad4 AMR exome AF: 0.337

Gnomad4 ASJ exome AF: 0.288

Gnomad4 EAS exome AF: 0.703

Gnomad4 SAS exome AF: 0.551

Gnomad4 FIN exome AF: 0.357

Gnomad4 NFE exome AF: 0.326

Gnomad4 OTH exome AF: 0.334

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

Gnomad4 AFR AF: 0.108

Gnomad4 AMR AF: 0.262

Gnomad4 ASJ AF: 0.286

Gnomad4 EAS AF: 0.656

Gnomad4 SAS AF: 0.567

Gnomad4 FIN AF: 0.379

Gnomad4 NFE AF: 0.319

Gnomad4 OTH AF: 0.256

Alfa AF: 0.300 Hom.: 5325

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

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 22, 2016	- -

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

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 19, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	8.4
DANN	Benign	0.68

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

Publications

LitVar

Other links and lift over

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