16-15071206-C-A

Position:

• chr16-15071206-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_018427.5(RRN3):​c.1174G>T​(p.Asp392Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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: RRN3 NM_018427.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.57

Genes affected

RRN3 (HGNC:30346): (RRN3 homolog, RNA polymerase I transcription factor) Enables RNA polymerase I core promoter sequence-specific DNA binding activity. Predicted to be involved in transcription initiation from RNA polymerase I promoter. Predicted to act upstream of or within several processes, including DNA-templated transcription, initiation; negative regulation of intrinsic apoptotic signaling pathway by p53 class mediator; and regulation of transcription, DNA-templated. Located in nucleolus. [provided by Alliance of Genome Resources, Apr 2022]

PDXDC1 (HGNC:28995): (pyridoxal dependent decarboxylase domain containing 1) Enables cadherin binding activity. Predicted to be involved in carboxylic acid metabolic process. Located in Golgi apparatus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3499009).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RRN3	NM_018427.5	c.1174G>T	p.Asp392Tyr	missense_variant	13/18	ENST00000198767.11	NP_060897.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RRN3	ENST00000198767.11	c.1174G>T	p.Asp392Tyr	missense_variant	13/18	1	NM_018427.5	ENSP00000198767.7

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 23, 2024

The c.1174G>T (p.D392Y) alteration is located in exon 13 (coding exon 13) of the RRN3 gene. This alteration results from a G to T substitution at nucleotide position 1174, causing the aspartic acid (D) at amino acid position 392 to be replaced by a tyrosine (Y). 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	Benign	0.26
BayesDel_addAF	Uncertain	0.073	D
BayesDel_noAF	Benign	-0.13
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Benign	0.32	T;.;T;.
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.97	D;D;D;D
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.35	T;T;T;T
MetaSVM	Benign	-0.74	T
MutationAssessor	Uncertain	2.2	M;.;.;.
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-4.2	D;D;D;D
REVEL	Benign	0.19
Sift	Uncertain	0.0040	D;D;D;D
Sift4G	Uncertain	0.024	D;D;D;D
Polyphen		0.97	D;.;D;.
Vest4		0.46
MutPred		0.51		Loss of disorder (P = 0.0202);Loss of disorder (P = 0.0202);.;.;
MVP		0.64
MPC		0.62
ClinPred		0.97	D
GERP RS		4.5
Varity_R		0.36
gMVP		0.62

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-15165063;