21-14964724-ATTCT-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM4 BS2

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
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 6.24

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]

ACMG classification

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 GnomAd at 19 AD gene.

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152134 Hom.: 0 Cov.: 32

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: 16 AN: 187230 Hom.: 0 AF XY: 0.0000702 AC XY: 7 AN XY: 99740

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.: 0 AF XY: 0.000114 AC XY: 78 AN XY: 684354

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: 19 AN: 152252 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74448

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.: 0

Bravo AF: 0.000136

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

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

Invitae

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

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

Other links and lift over

dbSNP: rs776126740; hg19: chr21-16337045;