Variant chr21-14964724-ATTCT-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM4BS2

The NM_003489.4(NRIP1):c.3465_3468del(p.Lys1155AsnfsTer15) variant causes a frameshift change. The variant allele was found at a frequency of 0.000113 in 1,539,272 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

NRIP1
NM_003489.4 frameshift

Scores

Not classified

Clinical Significance

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

Conservation

PhyloP100: 6.24

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 Likely_benign. Variant got -2 ACMG points.

PM4

Frameshift in the end of transcript resulting in stoplost. Downstream stopcodon found after 1297 codons.

BS2

High AC in GnomAd4 at 19 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NRIP1	NM_003489.4 linkuse as main transcript	c.3465_3468del	p.Lys1155AsnfsTer15	frameshift_variant	4/4	ENST00000318948.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
NRIP1	ENST00000318948.7 linkuse as main transcript	c.3465_3468del	p.Lys1155AsnfsTer15	frameshift_variant	4/4	2	NM_003489.4	P1
NRIP1	ENST00000400199.5 linkuse as main transcript	c.3465_3468del	p.Lys1155AsnfsTer15	frameshift_variant	3/3	3		P1
NRIP1	ENST00000400202.5 linkuse as main transcript	c.3465_3468del	p.Lys1155AsnfsTer15	frameshift_variant	3/3	5		P1

Frequencies

GnomAD3 genomes

AF:

0.000125

AC:

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000855

AC:

AN:

187230

Hom.:

AF XY:

0.0000702

AC XY:

AN XY:

99740

show subpopulations

Gnomad AFR exome

AF:

0.0000649

Gnomad AMR exome

AF:

0.0000942

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000356

Gnomad FIN exome

AF:

0.0000564

Gnomad NFE exome

AF:

0.0000548

Gnomad OTH exome

AF:

0.000233

GnomAD4 exome

AF:

0.000112

AC:

155

AN:

1387020

Hom.:

AF XY:

0.000114

AC XY:

AN XY:

684354

show subpopulations

Gnomad4 AFR exome

AF:

0.0000656

Gnomad4 AMR exome

AF:

0.000101

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000509

Gnomad4 SAS exome

AF:

0.000153

Gnomad4 FIN exome

AF:

0.0000198

Gnomad4 NFE exome

AF:

0.000119

Gnomad4 OTH exome

AF:

0.000122

GnomAD4 genome

AF:

0.000125

AC:

AN:

152252

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.0000963

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000162

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.000136

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jan 08, 2024

Variant summary: NRIP1 c.3465_3468delAGAA (p.Lys1155AsnfsX15) causes a frameshift which results in an extension of the protein, altering the last 4 amino acids in the native protein sequence and extending the protein by 10 amino acid. The molecular mechanism of disease attributed to NRIP1 is gain-of-function. The variant allele was found at a frequency of 0.00011 in 1539272 control chromosomes. To our knowledge, no occurrence of c.3465_3468delAGAA in individuals affected with Congenital Anomalies Of Kidney And Urinary Tract 3 and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 1723300). Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 24, 2022

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. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant has not been reported in the literature in individuals affected with NRIP1-related conditions. This variant is present in population databases (rs776126740, gnomAD 0.03%). This sequence change results in a frameshift in the NRIP1 gene (p.Lys1155Asnfs*15). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 4 amino acid(s) of the NRIP1 protein and extend the protein by 10 additional amino acid residues. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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