Genetic Variant NM_003321.5:c.817+13T>C (chr16-28844406-A-G) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.232

Publications

46 publications found

Variant links:

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

TUFM links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

Gene	Transcript	Tags	HGVSc	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.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.371

AC XY:

269937

AN XY:

727214

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

23529

47058

70588

94117

117646

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13520

27040

40560

54080

67600

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.342

AC:

51950

AN:

152030

Hom.:

9544

Cov.:

AF XY:

0.340

AC XY:

25261

AN XY:

74292

show subpopulations

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:

AN:

294

European-Non Finnish (NFE)

AF:

0.393

AC:

26677

AN:

67936

Other (OTH)

AF:

0.309

AC:

652

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1728

3456

5183

6911

8639

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

506

1012

1518

2024

2530

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

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

(source)

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)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over