12-57782806-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005726.6(TSFM):c.5C>T(p.Ser2Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00126 in 1,591,124 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S2S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0064 (11 hom., cov: 32)
  • Exomes 𝑓: 0.00072 (10 hom.)
• Consequence: TSFM NM_005726.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.439

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00456059).
• BP6: Variant 12-57782806-C-T is Benign according to our data. Variant chr12-57782806-C-T is described in ClinVar as [Benign]. Clinvar id is 703844.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00638 (971/152312) while in subpopulation AFR AF= 0.0226 (938/41572). AF 95% confidence interval is 0.0214. There are 11 homozygotes in gnomad4. There are 469 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSFM	NM_005726.6	c.5C>T	p.Ser2Leu	missense_variant	1/6	ENST00000652027.2
TSFM	NM_001172696.2	c.5C>T	p.Ser2Leu	missense_variant	1/7
TSFM	NM_001172697.2	c.5C>T	p.Ser2Leu	missense_variant	1/6
TSFM	NM_001172695.2	c.5C>T	p.Ser2Leu	missense_variant	1/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSFM	ENST00000652027.2	c.5C>T	p.Ser2Leu	missense_variant	1/6		NM_005726.6	P1

Frequencies

GnomAD3 genomes AF: 0.00637 AC: 970 AN: 152194 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.0226

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00158 AC: 339 AN: 214724 Hom.: 2 AF XY: 0.00115 AC XY: 133 AN XY: 115756

Gnomad AFR exome AF: 0.0230

Gnomad AMR exome AF: 0.00105

Gnomad ASJ exome AF: 0.000215

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000377

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000420

Gnomad OTH exome AF: 0.000554

GnomAD4 exome AF: 0.000717 AC: 1032 AN: 1438812 Hom.: 10 Cov.: 30 AF XY: 0.000601 AC XY: 429 AN XY: 713520

Gnomad4 AFR exome AF: 0.0232

Gnomad4 AMR exome AF: 0.00119

Gnomad4 ASJ exome AF: 0.000156

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000133

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000826

Gnomad4 OTH exome AF: 0.00180

GnomAD4 genome AF: 0.00638 AC: 971 AN: 152312 Hom.: 11 Cov.: 32 AF XY: 0.00630 AC XY: 469 AN XY: 74494

Gnomad4 AFR AF: 0.0226

Gnomad4 AMR AF: 0.00163

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00132 Hom.: 2

Bravo AF: 0.00778

ESP6500AA AF: 0.0238 AC: 105

ESP6500EA AF: 0.000117 AC: 1

ExAC AF: 0.00176 AC: 213

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fatal mitochondrial disease due to combined oxidative phosphorylation defect type 3 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 02, 2020	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	8.5
Dann	Benign	0.97
DEOGEN2	Benign	0.13	T;.;.;.;T;.
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.16	N
LIST_S2	Uncertain	0.87	D;D;D;D;D;D
MetaRNN	Benign	0.0046	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.20	N;N;N;.;.;N
MutationTaster	Benign	1.0	D;N;N;N;N;N;N
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.91	N;N;N;N;N;N
REVEL	Benign	0.057
Sift	Benign	0.18	T;T;T;T;T;T
Sift4G	Uncertain	0.022	D;D;D;D;D;D
Polyphen		0.0	B;.;B;.;.;.
Vest4		0.14
MVP		0.30
MPC		0.050
ClinPred		0.0098	T
GERP RS		2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.037
gMVP		0.56

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

Publications

LitVar

Other links and lift over

dbSNP: rs35957924; hg19: chr12-58176589;