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: Orphanet, Labcorp Genetics (formerly Invitae), G2P
• mitochondrial disease

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003321.5. 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
	TUFM	NM_003321.5	MANE Select	c.817+13T>C		intron	N/A	NP_003312.3
	TUFM	NM_001365360.2		c.817+13T>C		intron	N/A	NP_001352289.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUFM	ENST00000313511.8	TSL:1 MANE Select	c.817+13T>C		intron	N/A	ENSP00000322439.3	P49411
	TUFM	ENST00000916490.1		c.817+13T>C		intron	N/A	ENSP00000586549.1
	TUFM	ENST00000916489.1		c.817+13T>C		intron	N/A	ENSP00000586548.1

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Combined oxidative phosphorylation defect type 4 (2)

Computational scores

Source: dbNSFP v4.9

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;