NM_003677.5:c.-2A>C

Variant names:

• chr12-122753700-A-C
• rs368485489
• NM_003677.5:c.-2A>C

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_003677.5(DENR):​c.-2A>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000343 in 1,613,642 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.00032 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00035 (1 hom.)
• Consequence: DENR NM_003677.5 5_prime_UTR
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 2.61
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.3).
• BP6: Variant 12-122753700-A-C is Benign according to our data. Variant chr12-122753700-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 3045398.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DENR	NM_003677.5	c.-2A>C		5_prime_UTR_variant	Exon 2 of 8	ENST00000280557.11	NP_003668.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DENR	ENST00000280557.11	c.-2A>C		5_prime_UTR_variant	Exon 2 of 8	1	NM_003677.5	ENSP00000280557.6
DENR	ENST00000537955.1	n.112A>C		non_coding_transcript_exon_variant	Exon 2 of 2	2
DENR	ENST00000539463.1	n.132A>C		non_coding_transcript_exon_variant	Exon 2 of 4	2
DENR	ENST00000455982.2	c.-2A>C		5_prime_UTR_variant	Exon 2 of 8	5		ENSP00000413661.2

Frequencies

GnomAD3 genomes AF: 0.000315 AC: 48 AN: 152208 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000602

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000317 AC: 79 AN: 249096 AF XY: 0.000348

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.0000870

Gnomad ASJ exome AF: 0.000994

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000558

Gnomad OTH exome AF: 0.000331

GnomAD4 exome AF: 0.000346 AC: 506 AN: 1461434 Hom.: 1 Cov.: 30 AF XY: 0.000348 AC XY: 253 AN XY: 727016

African (AFR) AF: 0.0000299 AC: 1 AN: 33472

American (AMR) AF: 0.0000895 AC: 4 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.000918 AC: 24 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5766

European-Non Finnish (NFE) AF: 0.000414 AC: 460 AN: 1111638

Other (OTH) AF: 0.000232 AC: 14 AN: 60366

GnomAD4 genome AF: 0.000315 AC: 48 AN: 152208 Hom.: 0 Cov.: 32 AF XY: 0.000350 AC XY: 26 AN XY: 74356

African (AFR) AF: 0.0000241 AC: 1 AN: 41452

American (AMR) AF: 0.000131 AC: 2 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000602 AC: 41 AN: 68050

Other (OTH) AF: 0.000956 AC: 2 AN: 2092

Alfa AF: 0.000475 Hom.: 0

Bravo AF: 0.000306

EpiCase AF: 0.000927

EpiControl AF: 0.000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

DENR-related disorder Benign:1

Mar 01, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.30
CADD	Benign	17
DANN	Benign	0.88
PhyloP100		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=300/0	polymorphism

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: rs368485489; hg19: chr12-123238247;