chr21-14964750-C-T

Position:

chr21-14964750-C-T

Variant summary

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

The NM_003489.4(NRIP1):c.3443G>A(p.Gly1148Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000573 in 1,571,918 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

NRIP1
NM_003489.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.58

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:

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=0.04737228).

BS2

High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NRIP1	NM_003489.4 linkuse as main transcript	c.3443G>A	p.Gly1148Glu	missense_variant	4/4	ENST00000318948.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
NRIP1	ENST00000318948.7 linkuse as main transcript	c.3443G>A	p.Gly1148Glu	missense_variant	4/4	2	NM_003489.4	P1
NRIP1	ENST00000400199.5 linkuse as main transcript	c.3443G>A	p.Gly1148Glu	missense_variant	3/3	3		P1
NRIP1	ENST00000400202.5 linkuse as main transcript	c.3443G>A	p.Gly1148Glu	missense_variant	3/3	5		P1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000328

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:

0.00000471

AC:

AN:

212422

Hom.:

AF XY:

0.00000870

AC XY:

AN XY:

114902

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000399

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:

0.00000282

AC:

AN:

1419780

Hom.:

Cov.:

AF XY:

0.00000142

AC XY:

AN XY:

704820

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000886

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000171

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152138

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74338

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000328

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:

0.0000491

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 submitter

clinical testing

Ambry Genetics

Dec 09, 2023

The c.3443G>A (p.G1148E) alteration is located in exon 4 (coding exon 1) of the NRIP1 gene. This alteration results from a G to A substitution at nucleotide position 3443, causing the glycine (G) at amino acid position 1148 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 16, 2024

This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 1148 of the NRIP1 protein (p.Gly1148Glu). This variant is present in population databases (no rsID available, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with NRIP1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The glutamic acid amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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

0.20

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.59

CADD

Benign

DANN

Benign

0.87

DEOGEN2

Benign

0.033

T;T;T

Eigen

Benign

-0.26

Eigen_PC

Benign

-0.014

FATHMM_MKL

Benign

0.67

LIST_S2

Benign

0.77

T;.;.

M_CAP

Benign

0.0022

MetaRNN

Benign

0.047

T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.95

L;L;L

MutationTaster

Benign

0.99

D;D;D

PrimateAI

Uncertain

0.49

PROVEAN

Benign

1.7

N;N;N

REVEL

Benign

0.099

Sift

Benign

0.96

T;T;T

Sift4G

Benign

1.0

T;T;T

Polyphen

0.0090

B;B;B

Vest4

0.078

MutPred

0.40

Gain of solvent accessibility (P = 0.0145);Gain of solvent accessibility (P = 0.0145);Gain of solvent accessibility (P = 0.0145);

MVP

0.043

MPC

0.025

ClinPred

0.41

GERP RS

4.6

Varity_R

0.063

gMVP

0.22

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