rs4788099

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 46 publications found

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]

TUFM Gene-Disease associations (from GenCC):

• combined oxidative phosphorylation defect type 4

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 318747.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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

GnomAD2 exomes AF: 0.352 AC: 88247 AN: 251028 AF XY: 0.344

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 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

African (AFR) AF: 0.258 AC: 8625 AN: 33480

American (AMR) AF: 0.489 AC: 21869 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.270 AC: 7054 AN: 26136

East Asian (EAS) AF: 0.128 AC: 5069 AN: 39658

South Asian (SAS) AF: 0.228 AC: 19648 AN: 86258

European-Finnish (FIN) AF: 0.421 AC: 22495 AN: 53386

Middle Eastern (MID) AF: 0.206 AC: 1186 AN: 5768

European-Non Finnish (NFE) AF: 0.398 AC: 442494 AN: 1112006

Other (OTH) AF: 0.345 AC: 20859 AN: 60394

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

African (AFR) AF: 0.266 AC: 11034 AN: 41458

American (AMR) AF: 0.407 AC: 6214 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.268 AC: 930 AN: 3470

East Asian (EAS) AF: 0.121 AC: 626 AN: 5176

South Asian (SAS) AF: 0.218 AC: 1051 AN: 4830

European-Finnish (FIN) AF: 0.424 AC: 4477 AN: 10564

Middle Eastern (MID) AF: 0.224 AC: 66 AN: 294

European-Non Finnish (NFE) AF: 0.393 AC: 26677 AN: 67936

Other (OTH) AF: 0.309 AC: 652 AN: 2108

Alfa AF: 0.363 Hom.: 15161

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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
PhyloP100		0.23
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs4788099; hg19: chr16-28855727; COSMIC: COSV57948579; COSMIC: COSV57948579;