16-28842951-G-A

Variant names:

• chr16-28842951-G-A
• rs8754
• NM_003321.5:c.*24C>T

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.*24C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00455 in 1,613,506 control chromosomes in the GnomAD database, including 316 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (158 hom., cov: 32)
  • Exomes 𝑓: 0.0025 (158 hom.)
• Consequence: TUFM NM_003321.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.34
• Publications: 2 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: G2P, Labcorp Genetics (formerly Invitae), Orphanet
• 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=-0.86).
• BP6: Variant 16-28842951-G-A is Benign according to our data. Variant chr16-28842951-G-A is described in ClinVar as Benign. ClinVar VariationId is 318742.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0825 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.*24C>T		3_prime_UTR	Exon 10 of 10	NP_003312.3
	TUFM	NM_001365360.2		c.*24C>T		3_prime_UTR	Exon 10 of 10	NP_001352289.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUFM	ENST00000313511.8	TSL:1 MANE Select	c.*24C>T		3_prime_UTR	Exon 10 of 10	ENSP00000322439.3	P49411
	TUFM	ENST00000916490.1		c.*24C>T		3_prime_UTR	Exon 11 of 11	ENSP00000586549.1
	TUFM	ENST00000916489.1		c.*24C>T		3_prime_UTR	Exon 10 of 10	ENSP00000586548.1

Frequencies

GnomAD3 genomes AF: 0.0245 AC: 3718 AN: 152018 Hom.: 158 Cov.: 32

Gnomad AFR AF: 0.0847

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0113

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.0153

GnomAD2 exomes AF: 0.00635 AC: 1596 AN: 251442 AF XY: 0.00464

Gnomad AFR exome AF: 0.0896

Gnomad AMR exome AF: 0.00335

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000967

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.00247 AC: 3612 AN: 1461370 Hom.: 158 Cov.: 31 AF XY: 0.00214 AC XY: 1554 AN XY: 726980

African (AFR) AF: 0.0886 AC: 2965 AN: 33466

American (AMR) AF: 0.00436 AC: 195 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000174 AC: 15 AN: 86204

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00204 AC: 11 AN: 5402

European-Non Finnish (NFE) AF: 0.0000306 AC: 34 AN: 1111984

Other (OTH) AF: 0.00650 AC: 392 AN: 60352

GnomAD4 genome AF: 0.0246 AC: 3736 AN: 152136 Hom.: 158 Cov.: 32 AF XY: 0.0244 AC XY: 1816 AN XY: 74392

African (AFR) AF: 0.0849 AC: 3520 AN: 41470

American (AMR) AF: 0.0113 AC: 173 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 67978

Other (OTH) AF: 0.0152 AC: 32 AN: 2112

Alfa AF: 0.0161 Hom.: 33

Bravo AF: 0.0285

Asia WGS AF: 0.00866 AC: 30 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Combined oxidative phosphorylation defect type 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.45
DANN	Benign	0.42
PhyloP100		-1.3
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: rs8754; hg19: chr16-28854272;