21-14964890-C-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.114

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 -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=1, Benign=1}.
• BS2: High AC in GnomAd at 262 AD gene.

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NRIP1	ENST00000318948.7	c.3303G>C	p.Gln1101His	missense_variant	4/4	2	NM_003489.4	P1
NRIP1	ENST00000400199.5	c.3303G>C	p.Gln1101His	missense_variant	3/3	3		P1
NRIP1	ENST00000400202.5	c.3303G>C	p.Gln1101His	missense_variant	3/3	5		P1

Frequencies

GnomAD3 genomes AF: 0.00172 AC: 262 AN: 152166 Hom.: 2 Cov.: 32

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.: 1 AF XY: 0.000281 AC XY: 38 AN XY: 135224

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.: 1 Cov.: 33 AF XY: 0.000143 AC XY: 104 AN XY: 726780

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.: 2 Cov.: 32 AF XY: 0.00171 AC XY: 127 AN XY: 74472

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.: 0

Bravo AF: 0.00158

ESP6500AA AF: 0.00522 AC: 23

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000511 AC: 62

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 27, 2022

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, criteria provided, single submitter

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). -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 26, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.54
Cadd	Benign	13
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	D
LIST_S2	Benign	0.55	T;.;.
M_CAP	Benign	0.0097	T
MetaRNN	Benign	0.0059	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L;L;L
MutationTaster	Benign	0.65	D;D;D
PrimateAI	Benign	0.35	T
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	T
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

Other links and lift over

dbSNP: rs74503862; hg19: chr21-16337211;