12-122753766-A-C

Variant names:

• chr12-122753766-A-C
• rs200474298
• NM_003677.5:c.65A>C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_003677.5(DENR):​c.65A>C​(p.Lys22Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00144 in 1,613,924 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (4 hom.)
• Consequence: DENR NM_003677.5 missense
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 2.98
• Publications: 5 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.014574766).
• BP6: Variant 12-122753766-A-C is Benign according to our data. Variant chr12-122753766-A-C is described in ClinVar as Likely_benign. ClinVar VariationId is 3044403.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003677.5. 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
	DENR	NM_003677.5	MANE Select	c.65A>C	p.Lys22Thr	missense	Exon 2 of 8	NP_003668.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DENR	ENST00000280557.11	TSL:1 MANE Select	c.65A>C	p.Lys22Thr	missense	Exon 2 of 8	ENSP00000280557.6	O43583
	DENR	ENST00000963727.1		c.65A>C	p.Lys22Thr	missense	Exon 2 of 9	ENSP00000633786.1
	DENR	ENST00000963731.1		c.65A>C	p.Lys22Thr	missense	Exon 2 of 8	ENSP00000633790.1

Frequencies

GnomAD3 genomes AF: 0.00113 AC: 172 AN: 152242 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00132

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00185

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.00110 AC: 273 AN: 249214 AF XY: 0.00109

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.00113

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000743

Gnomad NFE exome AF: 0.00184

Gnomad OTH exome AF: 0.00149

GnomAD4 exome AF: 0.00147 AC: 2146 AN: 1461682 Hom.: 4 Cov.: 30 AF XY: 0.00148 AC XY: 1075 AN XY: 727126

African (AFR) AF: 0.0000896 AC: 3 AN: 33480

American (AMR) AF: 0.000917 AC: 41 AN: 44724

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

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.000581 AC: 31 AN: 53402

Middle Eastern (MID) AF: 0.000348 AC: 2 AN: 5748

European-Non Finnish (NFE) AF: 0.00179 AC: 1988 AN: 1111862

Other (OTH) AF: 0.00134 AC: 81 AN: 60372

GnomAD4 genome AF: 0.00113 AC: 172 AN: 152242 Hom.: 0 Cov.: 32 AF XY: 0.000995 AC XY: 74 AN XY: 74384

African (AFR) AF: 0.000169 AC: 7 AN: 41470

American (AMR) AF: 0.00131 AC: 20 AN: 15280

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5208

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00132 AC: 14 AN: 10628

Middle Eastern (MID) AF: 0.00316 AC: 1 AN: 316

European-Non Finnish (NFE) AF: 0.00185 AC: 126 AN: 68042

Other (OTH) AF: 0.00192 AC: 4 AN: 2088

Alfa AF: 0.00164 Hom.: 0

Bravo AF: 0.00105

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000259 AC: 1

ESP6500EA AF: 0.00228 AC: 19

ExAC AF: 0.00119 AC: 144

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00234

EpiControl AF: 0.00243

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	DENR-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.042	T
Eigen	Benign	-0.10
Eigen_PC	Benign	0.036
FATHMM_MKL	Benign	0.73	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.0054	T
MetaRNN	Benign	0.015	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		3.0
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.79	N
REVEL	Benign	0.25
Sift	Benign	0.19	T
Sift4G	Benign	0.12	T
Polyphen		0.0050	B
Vest4		0.27
MVP		0.45
MPC		0.66
ClinPred		0.027	T
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.10
gMVP		0.39
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs200474298; hg19: chr12-123238313; COSMIC: COSV54889535; COSMIC: COSV54889535;