16-15083524-C-T

Position:

• chr16-15083524-C-T

Variant summary

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

The NM_018427.5(RRN3):​c.655G>A​(p.Glu219Lys) 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. 13/21 in silico tools predict 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: 3.98

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]

RRN3 (HGNC:):

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=0.39838657).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RRN3	NM_018427.5	c.655G>A	p.Glu219Lys	missense_variant	8/18	ENST00000198767.11	NP_060897.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RRN3	ENST00000198767.11	c.655G>A	p.Glu219Lys	missense_variant	8/18	1	NM_018427.5	ENSP00000198767.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

Jun 20, 2024

The c.655G>A (p.E219K) alteration is located in exon 8 (coding exon 8) of the RRN3 gene. This alteration results from a G to A substitution at nucleotide position 655, causing the glutamic acid (E) at amino acid position 219 to be replaced by a lysine (K). 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	0.34
BayesDel_addAF	Benign	-0.019	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	22
DANN	Benign	0.87
DEOGEN2	Benign	0.047	T;.;T;.;.
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.086
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Pathogenic	0.97	D;D;D;D;D
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.40	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L;.;.;.;L
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-0.69	N;N;N;N;N
REVEL	Benign	0.13
Sift	Benign	0.74	T;T;T;T;T
Sift4G	Benign	0.87	T;T;T;T;T
Polyphen		0.41	B;.;B;.;.
Vest4		0.53
MutPred		0.45		Gain of MoRF binding (P = 0.0093);Gain of MoRF binding (P = 0.0093);.;.;Gain of MoRF binding (P = 0.0093);
MVP		0.74
MPC		0.29
ClinPred		0.57	D
GERP RS		4.5
Varity_R		0.22
gMVP		0.38

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: chr16-15177381;