Genetic Variant DENR:p.Leu68Ile (chr12-122762920-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_003677.5(DENR):c.202C>A(p.Leu68Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000288 in 1,388,326 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L68F) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000029 ( 0 hom. )

Consequence

DENR
NM_003677.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.92

Publications

0 publications found

Variant links:

Genes affected

DENR (HGNC:2769): (density regulated re-initiation and release factor) This gene encodes a protein whose expression was found to increase in cultured cells at high density but not during growth arrest. This gene was also shown to have increased expression in cells overexpressing HER-2/neu proto-oncogene. The protein contains an SUI1 domain. In budding yeast, SUI1 is a translation initiation factor that along with eIF-2 and the initiator tRNA-Met, directs the ribosome to the proper translation start site. Proteins similar to SUI have been found in mammals, insects, and plants. [provided by RefSeq, Jul 2008]

DENR links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.17122051).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DENR	NM_003677.5 link	c.202C>A	p.Leu68Ile	missense_variant	Exon 4 of 8	ENST00000280557.11	NP_003668.2	O43583A0A024RBR3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
DENR	ENST00000280557.11 link	c.202C>A	p.Leu68Ile	missense_variant	Exon 4 of 8	1	NM_003677.5	ENSP00000280557.6	O43583
DENR	ENST00000455982.2 link	c.202C>A	p.Leu68Ile	missense_variant	Exon 4 of 8	5		ENSP00000413661.2	F8VVL1
DENR	ENST00000539463.1 link	n.335C>A		non_coding_transcript_exon_variant	Exon 4 of 4	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000288

AC:

AN:

1388326

Hom.:

Cov.:

AF XY:

0.00000292

AC XY:

AN XY:

685112

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31196

American (AMR)

AF:

0.00

AC:

AN:

34324

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25050

East Asian (EAS)

AF:

0.00

AC:

AN:

35750

South Asian (SAS)

AF:

0.00

AC:

AN:

77386

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49206

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5680

European-Non Finnish (NFE)

AF:

0.00000373

AC:

AN:

1072166

Other (OTH)

AF:

0.00

AC:

AN:

57568

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Benign

-0.39

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.072

T;.

Eigen

Benign

0.17

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.79

T;T

M_CAP

Benign

0.016

MetaRNN

Benign

0.17

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.2

M;.

PhyloP100

3.9

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-0.86

N;N

REVEL

Benign

0.10

Sift

Benign

0.099

T;T

Sift4G

Benign

0.19

T;T

Polyphen

0.092

B;P

Vest4

0.44

MutPred

0.33

Gain of catalytic residue at N72 (P = 0.067);Gain of catalytic residue at N72 (P = 0.067);

MVP

0.32

MPC

0.77

ClinPred

0.68

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.31

gMVP

0.30

Mutation Taster

=26/74

disease causing

(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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12-122762920-C-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over