chr21-14964890-C-G

Position:

chr21-14964890-C-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_003489.4(NRIP1):c.3303G>C(p.Gln1101His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000322 in 1,613,220 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0017 ( 2 hom., cov: 32)

Exomes 𝑓: 0.00018 ( 1 hom. )

Consequence

NRIP1
NM_003489.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 0.114

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]

NRIP1 links:

ENSG00000235609 (HGNC:):

ENSG00000235609 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0058936477).

BP6

Variant 21-14964890-C-G is Benign according to our data. Variant chr21-14964890-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 726431.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=2}.

BS2

High AC in GnomAd4 at 262 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NRIP1	NM_003489.4 link	c.3303G>C	p.Gln1101His	missense_variant	4/4	ENST00000318948.7	NP_003480.2	P48552A8K171

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
NRIP1	ENST00000318948.7 link	c.3303G>C	p.Gln1101His	missense_variant	4/4	2	NM_003489.4	ENSP00000327213.4	P48552
NRIP1	ENST00000400199.5 link	c.3303G>C	p.Gln1101His	missense_variant	3/3	3		ENSP00000383060.1	P48552
NRIP1	ENST00000400202.5 link	c.3303G>C	p.Gln1101His	missense_variant	3/3	5		ENSP00000383063.1	P48552
ENSG00000235609	ENST00000432230.6 link	n.87+49454G>C		intron_variant		5

Frequencies

GnomAD3 genomes

AF:

0.00172

AC:

262

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00594

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000720

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.000958

GnomAD3 exomes

AF:

0.000432

AC:

108

AN:

250170

Hom.:

AF XY:

0.000281

AC XY:

AN XY:

135224

show subpopulations

Gnomad AFR exome

AF:

0.00628

Gnomad AMR exome

AF:

0.000145

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:

0.000164

GnomAD4 exome

AF:

0.000177

AC:

258

AN:

1460936

Hom.:

Cov.:

AF XY:

0.000143

AC XY:

104

AN XY:

726780

show subpopulations

Gnomad4 AFR exome

AF:

0.00677

Gnomad4 AMR exome

AF:

0.000135

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.000298

GnomAD4 genome

AF:

0.00172

AC:

262

AN:

152284

Hom.:

Cov.:

AF XY:

0.00171

AC XY:

127

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.00592

Gnomad4 AMR

AF:

0.000719

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.000948

Alfa

AF:

0.000218

Hom.:

Bravo

AF:

0.00158

ESP6500AA

AF:

0.00522

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000511

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 26, 2023	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 20, 2024

The c.3303G>C (p.Q1101H) alteration is located in exon 4 (coding exon 1) of the NRIP1 gene. This alteration results from a G to C substitution at nucleotide position 3303, causing the glutamine (Q) at amino acid position 1101 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

NRIP1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 22, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.54

CADD

Benign

DANN

Benign

0.92

DEOGEN2

Benign

0.18

T;T;T

Eigen

Benign

-0.098

Eigen_PC

Benign

-0.10

FATHMM_MKL

Benign

0.68

LIST_S2

Benign

0.55

T;.;.

M_CAP

Benign

0.0097

MetaRNN

Benign

0.0059

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.6

L;L;L

PrimateAI

Benign

0.35

PROVEAN

Uncertain

-2.7

D;D;D

REVEL

Benign

0.070

Sift

Benign

0.055

T;T;T

Sift4G

Uncertain

0.044

D;D;D

Polyphen

0.73

P;P;P

Vest4

0.087

MutPred

0.088

Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);

MVP

0.30

MPC

0.021

ClinPred

0.029

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.13

gMVP

0.28

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over