21-14964763-A-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_003489.4(NRIP1):c.3430T>G(p.Tyr1144Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00116 in 1,582,388 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00086 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (2 hom.)
• Consequence: NRIP1 NM_003489.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.36

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 Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.04485318).
• BP6: Variant 21-14964763-A-C is Benign according to our data. Variant chr21-14964763-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 1049819.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 131 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NRIP1	NM_003489.4	c.3430T>G	p.Tyr1144Asp	missense_variant	4/4	ENST00000318948.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NRIP1	ENST00000318948.7	c.3430T>G	p.Tyr1144Asp	missense_variant	4/4	2	NM_003489.4	P1
NRIP1	ENST00000400199.5	c.3430T>G	p.Tyr1144Asp	missense_variant	3/3	3		P1
NRIP1	ENST00000400202.5	c.3430T>G	p.Tyr1144Asp	missense_variant	3/3	5		P1

Frequencies

GnomAD3 genomes AF: 0.000861 AC: 131 AN: 152164 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000983

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00129

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.000875 AC: 193 AN: 220458 Hom.: 0 AF XY: 0.000805 AC XY: 96 AN XY: 119328

Gnomad AFR exome AF: 0.000127

Gnomad AMR exome AF: 0.000714

Gnomad ASJ exome AF: 0.00347

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000411

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00134

Gnomad OTH exome AF: 0.000966

GnomAD4 exome AF: 0.00120 AC: 1709 AN: 1430106 Hom.: 2 Cov.: 32 AF XY: 0.00117 AC XY: 834 AN XY: 710750

Gnomad4 AFR exome AF: 0.000254

Gnomad4 AMR exome AF: 0.000784

Gnomad4 ASJ exome AF: 0.00370

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000499

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00137

Gnomad4 OTH exome AF: 0.00110

GnomAD4 genome AF: 0.000860 AC: 131 AN: 152282 Hom.: 0 Cov.: 32 AF XY: 0.000725 AC XY: 54 AN XY: 74472

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.000981

Gnomad4 ASJ AF: 0.00403

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00129

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.00115 Hom.: 0

Bravo AF: 0.000948

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00151 AC: 13

ExAC AF: 0.000890 AC: 108

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The NRIP1 p.Y1144D variant was not identified in the literature nor was it identified in ClinVar. The variant was identified in dbSNP (ID: rs61733441) and in control databases in 210 of 251860 chromosomes at a frequency of 0.0008338, and was observed at the highest frequency in the European (non-Finnish) population in 150 of 119394 chromosomes (freq: 0.001256) (Genome Aggregation Database March 6, 2019, v2.1.1). This frequency is greater than expected for the rare, autosomal dominant congenital anomalies of kidney and urinary tract 3 condition associated with NRIP1 variants. The p.Y1144 residue is conserved in mammals and computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	May 22, 2023	- -

NRIP1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 18, 2020

This variant is classified as likely 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	Uncertain	0.35
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Uncertain	0.010
Cadd	Uncertain	23
Dann	Uncertain	0.99
DEOGEN2	Benign	0.25	T;T;T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.75	T;.;.
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.045	T;T;T
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.4	M;M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.49	T
PROVEAN	Pathogenic	-6.6	D;D;D
REVEL	Uncertain	0.34
Sift	Uncertain	0.010	D;D;D
Sift4G	Uncertain	0.016	D;D;D
Polyphen		0.98	D;D;D
Vest4		0.69
MVP		0.63
MPC		0.15
ClinPred		0.11	T
GERP RS		5.7
Varity_R		0.55
gMVP		0.41

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: rs61733441; hg19: chr21-16337084;