21-14964949-G-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_003489.4(NRIP1):​c.3244C>G​(p.Arg1082Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000657 in 1,613,718 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00043 ( 1 hom., cov: 32)
Exomes 𝑓: 0.000028 ( 0 hom. )

Consequence

NRIP1
NM_003489.4 missense

Scores

6
13

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 1.75
Variant links:
Genes affected
NRIP1 (HGNC:8001): (nuclear receptor interacting protein 1) Nuclear receptor interacting protein 1 (NRIP1) is a nuclear protein that specifically interacts with the hormone-dependent activation domain AF2 of nuclear receptors. Also known as RIP140, this protein modulates transcriptional activity of the estrogen receptor. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.038786262).
BS2
High AC in GnomAd4 at 65 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
NRIP1NM_003489.4 linkuse as main transcriptc.3244C>G p.Arg1082Gly missense_variant 4/4 ENST00000318948.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
NRIP1ENST00000318948.7 linkuse as main transcriptc.3244C>G p.Arg1082Gly missense_variant 4/42 NM_003489.4 P1
NRIP1ENST00000400199.5 linkuse as main transcriptc.3244C>G p.Arg1082Gly missense_variant 3/33 P1
NRIP1ENST00000400202.5 linkuse as main transcriptc.3244C>G p.Arg1082Gly missense_variant 3/35 P1

Frequencies

GnomAD3 genomes
AF:
0.000427
AC:
65
AN:
152130
Hom.:
1
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00419
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000108
AC:
27
AN:
251008
Hom.:
0
AF XY:
0.000111
AC XY:
15
AN XY:
135652
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000781
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000281
AC:
41
AN:
1461588
Hom.:
0
Cov.:
33
AF XY:
0.0000248
AC XY:
18
AN XY:
727110
show subpopulations
Gnomad4 AFR exome
AF:
0.0000598
Gnomad4 AMR exome
AF:
0.000783
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000497
GnomAD4 genome
AF:
0.000427
AC:
65
AN:
152130
Hom.:
1
Cov.:
32
AF XY:
0.000646
AC XY:
48
AN XY:
74322
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00419
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.000416

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJan 23, 2023The c.3244C>G (p.R1082G) alteration is located in exon 4 (coding exon 1) of the NRIP1 gene. This alteration results from a C to G substitution at nucleotide position 3244, causing the arginine (R) at amino acid position 1082 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpAug 27, 2023This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 1082 of the NRIP1 protein (p.Arg1082Gly). This variant is present in population databases (no rsID available, gnomAD 0.08%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with NRIP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 2159986). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.079
BayesDel_addAF
Benign
-0.40
T
BayesDel_noAF
Benign
-0.43
CADD
Benign
18
DANN
Uncertain
0.99
DEOGEN2
Benign
0.18
T;T;T
Eigen
Benign
0.055
Eigen_PC
Benign
0.15
FATHMM_MKL
Uncertain
0.84
D
LIST_S2
Benign
0.70
T;.;.
M_CAP
Benign
0.0078
T
MetaRNN
Benign
0.039
T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Uncertain
2.1
M;M;M
MutationTaster
Benign
0.81
N;N;N
PrimateAI
Benign
0.30
T
PROVEAN
Uncertain
-3.0
D;D;D
REVEL
Benign
0.10
Sift
Uncertain
0.0080
D;D;D
Sift4G
Uncertain
0.017
D;D;D
Polyphen
0.71
P;P;P
Vest4
0.20
MutPred
0.20
Loss of solvent accessibility (P = 0.0329);Loss of solvent accessibility (P = 0.0329);Loss of solvent accessibility (P = 0.0329);
MVP
0.17
MPC
0.024
ClinPred
0.16
T
GERP RS
4.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.24
gMVP
0.23

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1329599593; hg19: chr21-16337270; API