NM_003321.5:c.817+13T>C

Variant names:

• chr16-28844406-A-G
• rs4788099
• NM_003321.5:c.817+13T>C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003321.5(TUFM):​c.817+13T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.373 in 1,613,840 control chromosomes in the GnomAD database, including 116,907 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.34 (9544 hom., cov: 32)
  • Exomes 𝑓: 0.38 (107363 hom.)
• Consequence: TUFM NM_003321.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.232

Genes affected

TUFM (HGNC:12420): (Tu translation elongation factor, mitochondrial) This gene encodes a protein which participates in protein translation in mitochondria. Mutations in this gene have been associated with combined oxidative phosphorylation deficiency resulting in lactic acidosis and fatal encephalopathy. A pseudogene has been identified on chromosome 17. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 16-28844406-A-G is Benign according to our data. Variant chr16-28844406-A-G is described in ClinVar as [Benign]. Clinvar id is 318747.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-28844406-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.398 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TUFM	NM_003321.5	c.817+13T>C		intron_variant	Intron 6 of 9	ENST00000313511.8	NP_003312.3
TUFM	NM_001365360.2	c.817+13T>C		intron_variant	Intron 6 of 9		NP_001352289.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TUFM	ENST00000313511.8	c.817+13T>C		intron_variant	Intron 6 of 9	1	NM_003321.5	ENSP00000322439.3
TUFM	ENST00000565012.1	n.*344+13T>C		intron_variant	Intron 5 of 6	5		ENSP00000455007.1
TUFM	ENST00000569217.1	n.-74T>C		upstream_gene_variant		2
TUFM	ENST00000561644.1	n.*220T>C		downstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.341 AC: 51857 AN: 151912 Hom.: 9515 Cov.: 32

Gnomad AFR AF: 0.265

Gnomad AMI AF: 0.245

Gnomad AMR AF: 0.406

Gnomad ASJ AF: 0.268

Gnomad EAS AF: 0.121

Gnomad SAS AF: 0.217

Gnomad FIN AF: 0.424

Gnomad MID AF: 0.231

Gnomad NFE AF: 0.393

Gnomad OTH AF: 0.305

GnomAD3 exomes AF: 0.352 AC: 88247 AN: 251028 Hom.: 17165 AF XY: 0.344 AC XY: 46635 AN XY: 135692

Gnomad AFR exome AF: 0.271

Gnomad AMR exome AF: 0.487

Gnomad ASJ exome AF: 0.274

Gnomad EAS exome AF: 0.103

Gnomad SAS exome AF: 0.228

Gnomad FIN exome AF: 0.425

Gnomad NFE exome AF: 0.388

Gnomad OTH exome AF: 0.347

GnomAD4 exome AF: 0.376 AC: 549299 AN: 1461810 Hom.: 107363 Cov.: 66 AF XY: 0.371 AC XY: 269937 AN XY: 727214

Gnomad4 AFR exome AF: 0.258

Gnomad4 AMR exome AF: 0.489

Gnomad4 ASJ exome AF: 0.270

Gnomad4 EAS exome AF: 0.128

Gnomad4 SAS exome AF: 0.228

Gnomad4 FIN exome AF: 0.421

Gnomad4 NFE exome AF: 0.398

Gnomad4 OTH exome AF: 0.345

GnomAD4 genome AF: 0.342 AC: 51950 AN: 152030 Hom.: 9544 Cov.: 32 AF XY: 0.340 AC XY: 25261 AN XY: 74292

Gnomad4 AFR AF: 0.266

Gnomad4 AMR AF: 0.407

Gnomad4 ASJ AF: 0.268

Gnomad4 EAS AF: 0.121

Gnomad4 SAS AF: 0.218

Gnomad4 FIN AF: 0.424

Gnomad4 NFE AF: 0.393

Gnomad4 OTH AF: 0.309

Alfa AF: 0.373 Hom.: 11450

Bravo AF: 0.339

Asia WGS AF: 0.275 AC: 955 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Combined oxidative phosphorylation defect type 4 Benign:2

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	-0.84
CADD	Benign	6.5
DANN	Benign	0.53
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs4788099; hg19: chr16-28855727; COSMIC: COSV57948579; COSMIC: COSV57948579;