12-57783654-C-T

Variant names:

• chr12-57783654-C-T
• rs2014886
• NM_005726.6:c.231+371C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 4P and 8B. PVS1_Strong BA1

The ENST00000546504.1(ENSG00000257921):​c.288+2C>T variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.326 in 571,300 control chromosomes in the GnomAD database, including 35,496 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.27 (6763 hom., cov: 32)
  • Exomes 𝑓: 0.35 (28733 hom.)
• Consequence: ENSG00000257921 ENST00000546504.1 splice_donor, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.210
• Publications: 19 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: Labcorp Genetics (formerly Invitae), Orphanet
• Leigh syndrome

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen

ENSG00000257921 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.101876676 fraction of the gene. Cryptic splice site detected, with MaxEntScore 7.8, offset of 0 (no position change), new splice context is: atgGTacga. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• 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: ENST00000546504.1. 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.231+371C>T		intron	N/A	NP_005717.3
	TSFM	NM_001172696.2		c.231+371C>T		intron	N/A	NP_001166167.1
	TSFM	NM_001172697.2		c.231+371C>T		intron	N/A	NP_001166168.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSFM	ENST00000652027.2	MANE Select	c.231+371C>T		intron	N/A	ENSP00000499171.2
	TSFM	ENST00000323833.12	TSL:1	c.231+371C>T		intron	N/A	ENSP00000313877.8
	TSFM	ENST00000543727.5	TSL:1	c.231+371C>T		intron	N/A	ENSP00000439342.1

Frequencies

GnomAD3 genomes AF: 0.266 AC: 40297 AN: 151694 Hom.: 6761 Cov.: 32

Gnomad AFR AF: 0.0794

Gnomad AMI AF: 0.385

Gnomad AMR AF: 0.256

Gnomad ASJ AF: 0.286

Gnomad EAS AF: 0.651

Gnomad SAS AF: 0.498

Gnomad FIN AF: 0.376

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.317

Gnomad OTH AF: 0.240

GnomAD2 exomes AF: 0.364 AC: 47977 AN: 131796 AF XY: 0.375

Gnomad AFR exome AF: 0.0733

Gnomad AMR exome AF: 0.337

Gnomad ASJ exome AF: 0.279

Gnomad EAS exome AF: 0.627

Gnomad FIN exome AF: 0.372

Gnomad NFE exome AF: 0.317

Gnomad OTH exome AF: 0.300

GnomAD4 exome AF: 0.348 AC: 145777 AN: 419488 Hom.: 28733 Cov.: 0 AF XY: 0.358 AC XY: 82951 AN XY: 231408

African (AFR) AF: 0.0739 AC: 943 AN: 12764

American (AMR) AF: 0.328 AC: 9921 AN: 30268

Ashkenazi Jewish (ASJ) AF: 0.279 AC: 4368 AN: 15654

East Asian (EAS) AF: 0.681 AC: 12323 AN: 18106

South Asian (SAS) AF: 0.489 AC: 29643 AN: 60576

European-Finnish (FIN) AF: 0.348 AC: 7699 AN: 22104

Middle Eastern (MID) AF: 0.177 AC: 590 AN: 3324

European-Non Finnish (NFE) AF: 0.313 AC: 73474 AN: 234552

Other (OTH) AF: 0.308 AC: 6816 AN: 22140

GnomAD4 genome AF: 0.265 AC: 40304 AN: 151812 Hom.: 6763 Cov.: 32 AF XY: 0.274 AC XY: 20304 AN XY: 74174

African (AFR) AF: 0.0792 AC: 3278 AN: 41378

American (AMR) AF: 0.256 AC: 3912 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.286 AC: 992 AN: 3472

East Asian (EAS) AF: 0.651 AC: 3357 AN: 5156

South Asian (SAS) AF: 0.499 AC: 2400 AN: 4812

European-Finnish (FIN) AF: 0.376 AC: 3942 AN: 10484

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

European-Non Finnish (NFE) AF: 0.317 AC: 21527 AN: 67930

Other (OTH) AF: 0.238 AC: 502 AN: 2108

Alfa AF: 0.275 Hom.: 1225

Bravo AF: 0.247

TwinsUK AF: 0.301 AC: 1115

ALSPAC AF: 0.328 AC: 1263

ExAC AF: 0.324 AC: 5600

Asia WGS AF: 0.518 AC: 1798 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.90	T
BayesDel_noAF	Benign	-0.92
CADD	Benign	2.3
DANN	Benign	0.25
Eigen	Benign	-0.062
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.010	N
PhyloP100		0.21
GERP RS		0.12
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.82		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.21		Position offset: -39
DS_DG_spliceai		0.82		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2014886; hg19: chr12-58177437;