14-90286385-G-T

Position:

• chr14-90286385-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_017970.4(NRDE2):​c.3266C>A​(p.Pro1089His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NRDE2 NM_017970.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.20

Genes affected

NRDE2 (HGNC:20186): (NRDE-2, necessary for RNA interference, domain containing) Involved in several processes, including RNA splicing; negative regulation of RNA catabolic process; and positive regulation of RNA export from nucleus. Located in nuclear speck and nucleolus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.884

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NRDE2	NM_017970.4	c.3266C>A	p.Pro1089His	missense_variant	12/14	ENST00000354366.8	NP_060440.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NRDE2	ENST00000354366.8	c.3266C>A	p.Pro1089His	missense_variant	12/14	1	NM_017970.4	ENSP00000346335	P1
NRDE2	ENST00000553409.5	c.*2791C>A		3_prime_UTR_variant, NMD_transcript_variant	10/12	1		ENSP00000451025
NRDE2	ENST00000556189.5	c.*1744C>A		3_prime_UTR_variant, NMD_transcript_variant	8/10	1		ENSP00000452107
NRDE2	ENST00000555903.1	n.777C>A		non_coding_transcript_exon_variant	2/3	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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 16, 2023

The c.3266C>A (p.P1089H) alteration is located in exon 12 (coding exon 12) of the NRDE2 gene. This alteration results from a C to A substitution at nucleotide position 3266, causing the proline (P) at amino acid position 1089 to be replaced by a histidine (H). 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	0.84
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Uncertain	0.36	D
MutationAssessor	Pathogenic	3.2	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-3.3	D
REVEL	Pathogenic	0.81
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.90
MutPred		0.59		Gain of catalytic residue at L1090 (P = 0);
MVP		0.92
MPC		0.42
ClinPred		0.99	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.43
gMVP		0.72

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: chr14-90752729;