12-57782806-C-T

Variant names:

• chr12-57782806-C-T
• rs35957924
• NM_005726.6:c.5C>T

Variant summary

Our verdict is Benign. The variant received -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. 15/20 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:5
• Conservation: PhyloP100: -0.439
• Publications: 5 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: Benign. The variant received -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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 11 AR gene

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.5C>T	p.Ser2Leu	missense	Exon 1 of 6	NP_005717.3
	TSFM	NM_001172696.2		c.5C>T	p.Ser2Leu	missense	Exon 1 of 7	NP_001166167.1	P43897-2
	TSFM	NM_001172697.2		c.5C>T	p.Ser2Leu	missense	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.5C>T	p.Ser2Leu	missense	Exon 1 of 6	ENSP00000499171.2	P43897-1
	TSFM	ENST00000323833.12	TSL:1	c.5C>T	p.Ser2Leu	missense	Exon 1 of 7	ENSP00000313877.8	P43897-2
	TSFM	ENST00000543727.5	TSL:1	c.5C>T	p.Ser2Leu	missense	Exon 1 of 6	ENSP00000439342.1	P43897-4

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

GnomAD2 exomes AF: 0.00158 AC: 339 AN: 214724 AF XY: 0.00115

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 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

African (AFR) AF: 0.0232 AC: 764 AN: 32994

American (AMR) AF: 0.00119 AC: 49 AN: 41238

Ashkenazi Jewish (ASJ) AF: 0.000156 AC: 4 AN: 25674

East Asian (EAS) AF: 0.00 AC: 0 AN: 38272

South Asian (SAS) AF: 0.000133 AC: 11 AN: 82626

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51190

Middle Eastern (MID) AF: 0.00105 AC: 6 AN: 5734

European-Non Finnish (NFE) AF: 0.0000826 AC: 91 AN: 1101604

Other (OTH) AF: 0.00180 AC: 107 AN: 59480

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

African (AFR) AF: 0.0226 AC: 938 AN: 41572

American (AMR) AF: 0.00163 AC: 25 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68026

Other (OTH) AF: 0.00142 AC: 3 AN: 2106

Alfa AF: 0.00183 Hom.: 3

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Fatal mitochondrial disease due to combined oxidative phosphorylation defect type 3 (2)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.16	N
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.0046	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.20	N
PhyloP100		-0.44
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.91	N
REVEL	Benign	0.057
Sift	Benign	0.18	T
Sift4G	Uncertain	0.022	D
Polyphen		0.0	B
Vest4		0.14
MVP		0.30
MPC		0.050
ClinPred		0.0098	T
GERP RS		2.2
PromoterAI		-0.25	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.037
gMVP		0.56
Mutation Taster		=98/2	polymorphism

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: rs35957924; hg19: chr12-58176589;