chr12-122765379-A-C

Variant names:

• chr12-122765379-A-C
• NM_003677.5:c.287A>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003677.5(DENR):​c.287A>C​(p.Gln96Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DENR NM_003677.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.52
• 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: 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=0.18674085).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DENR	NM_003677.5	c.287A>C	p.Gln96Pro	missense_variant	Exon 5 of 8	ENST00000280557.11	NP_003668.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DENR	ENST00000280557.11	c.287A>C	p.Gln96Pro	missense_variant	Exon 5 of 8	1	NM_003677.5	ENSP00000280557.6
DENR	ENST00000455982.2	c.287A>C	p.Gln96Pro	missense_variant	Exon 5 of 8	5		ENSP00000413661.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 27, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.287A>C (p.Q96P) alteration is located in exon 5 (coding exon 4) of the DENR gene. This alteration results from a A to C substitution at nucleotide position 287, causing the glutamine (Q) at amino acid position 96 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Uncertain	0.073	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.30	T;.
Eigen	Benign	0.049
Eigen_PC	Benign	0.15
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.85	D;D
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.19	T;T
MetaSVM	Benign	-0.67	T
MutationAssessor	Uncertain	2.5	M;.
PhyloP100		4.5
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-5.5	D;D
REVEL	Uncertain	0.34
Sift	Uncertain	0.020	D;D
Sift4G	Uncertain	0.041	D;D
Polyphen		0.078	B;B
Vest4		0.37
MutPred		0.37		Gain of catalytic residue at R101 (P = 0.0136);Gain of catalytic residue at R101 (P = 0.0136);
MVP		0.55
MPC		0.67
ClinPred		0.99	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.84
gMVP		0.66
Mutation Taster		=19/81	disease causing

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

hg19: chr12-123249926;