12-122765393-A-T

Variant names:

• chr12-122765393-A-T
• rs71456774
• NM_003677.5:c.295+6A>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_003677.5(DENR):​c.295+6A>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000737 in 1,546,152 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.00032 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000047 (0 hom.)
• Consequence: DENR NM_003677.5 splice_region, intron
• Scores: Splicing: ADA: 0.00008579
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.203
• 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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 12-122765393-A-T is Benign according to our data. Variant chr12-122765393-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 3039206.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.295+6A>T		splice_region_variant, intron_variant	Intron 5 of 7	ENST00000280557.11	NP_003668.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DENR	ENST00000280557.11	c.295+6A>T		splice_region_variant, intron_variant	Intron 5 of 7	1	NM_003677.5	ENSP00000280557.6
DENR	ENST00000455982.2	c.295+6A>T		splice_region_variant, intron_variant	Intron 5 of 7	5		ENSP00000413661.2

Frequencies

GnomAD3 genomes AF: 0.000315 AC: 48 AN: 152180 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00109

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000824 AC: 13 AN: 157714 AF XY: 0.0000602

Gnomad AFR exome AF: 0.00110

Gnomad AMR exome AF: 0.000122

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000474 AC: 66 AN: 1393854 Hom.: 0 Cov.: 28 AF XY: 0.0000509 AC XY: 35 AN XY: 688006

African (AFR) AF: 0.00149 AC: 47 AN: 31448

American (AMR) AF: 0.000112 AC: 4 AN: 35568

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25134

East Asian (EAS) AF: 0.00 AC: 0 AN: 35724

South Asian (SAS) AF: 0.0000506 AC: 4 AN: 79034

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49326

Middle Eastern (MID) AF: 0.000176 AC: 1 AN: 5692

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1074104

Other (OTH) AF: 0.000173 AC: 10 AN: 57824

GnomAD4 genome AF: 0.000315 AC: 48 AN: 152298 Hom.: 0 Cov.: 32 AF XY: 0.000269 AC XY: 20 AN XY: 74478

African (AFR) AF: 0.00108 AC: 45 AN: 41552

American (AMR) AF: 0.0000654 AC: 1 AN: 15288

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.000340

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

DENR-related disorder Benign:1

May 21, 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	-0.75
CADD	Benign	6.3
DANN	Benign	0.84
PhyloP100		0.20
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000086
dbscSNV1_RF	Benign	0.0060
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: rs71456774; hg19: chr12-123249940;