chr12-57786633-G-C

Variant names:

• chr12-57786633-G-C
• rs724834
• NM_005726.6:c.360+342G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005726.6(TSFM):​c.360+342G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.266 in 152,168 control chromosomes in the GnomAD database, including 6,794 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.27 (6794 hom., cov: 32)
• Consequence: TSFM NM_005726.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.325
• Publications: 14 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.633 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.360+342G>C		intron	N/A	NP_005717.3
	TSFM	NM_001172696.2		c.360+342G>C		intron	N/A	NP_001166167.1
	TSFM	NM_001172697.2		c.360+342G>C		intron	N/A	NP_001166168.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSFM	ENST00000652027.2	MANE Select	c.360+342G>C		intron	N/A	ENSP00000499171.2
	TSFM	ENST00000323833.12	TSL:1	c.360+342G>C		intron	N/A	ENSP00000313877.8
	TSFM	ENST00000543727.5	TSL:1	c.360+342G>C		intron	N/A	ENSP00000439342.1

Frequencies

GnomAD3 genomes AF: 0.266 AC: 40407 AN: 152050 Hom.: 6792 Cov.: 32

Gnomad AFR AF: 0.0793

Gnomad AMI AF: 0.385

Gnomad AMR AF: 0.256

Gnomad ASJ AF: 0.286

Gnomad EAS AF: 0.651

Gnomad SAS AF: 0.497

Gnomad FIN AF: 0.378

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.317

Gnomad OTH AF: 0.239

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.266 AC: 40414 AN: 152168 Hom.: 6794 Cov.: 32 AF XY: 0.274 AC XY: 20384 AN XY: 74386

African (AFR) AF: 0.0791 AC: 3287 AN: 41544

American (AMR) AF: 0.256 AC: 3917 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.286 AC: 991 AN: 3470

East Asian (EAS) AF: 0.651 AC: 3376 AN: 5186

South Asian (SAS) AF: 0.498 AC: 2401 AN: 4820

European-Finnish (FIN) AF: 0.378 AC: 3992 AN: 10562

Middle Eastern (MID) AF: 0.146 AC: 43 AN: 294

European-Non Finnish (NFE) AF: 0.317 AC: 21554 AN: 67990

Other (OTH) AF: 0.237 AC: 502 AN: 2114

Alfa AF: 0.166 Hom.: 366

Bravo AF: 0.247

Asia WGS AF: 0.519 AC: 1802 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	8.4
DANN	Benign	0.68
PhyloP100		0.33
Mutation Taster		=100/0	polymorphism (auto)

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: rs724834; hg19: chr12-58180416;