rs2229742

Variant names:

• chr21-14966851-G-C
• rs2229742
• NM_003489.4:c.1342C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003489.4(NRIP1):​c.1342C>G​(p.Arg448Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0926 in 1,613,906 control chromosomes in the GnomAD database, including 7,528 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R448L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.070 (501 hom., cov: 32)
  • Exomes 𝑓: 0.095 (7027 hom.)
• Consequence: NRIP1 NM_003489.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.92
• Publications: 59 publications found

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]

ASMER1 (HGNC:53135): (adipocyte associated metabolic related lncRNA 1)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.001825124).
• BP6: Variant 21-14966851-G-C is Benign according to our data. Variant chr21-14966851-G-C is described in ClinVar as Benign. ClinVar VariationId is 1593778.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.104 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003489.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRIP1	NM_003489.4	MANE Select	c.1342C>G	p.Arg448Gly	missense	Exon 4 of 4	NP_003480.2
	NRIP1	NM_001439275.1		c.1342C>G	p.Arg448Gly	missense	Exon 5 of 5	NP_001426204.1
	NRIP1	NM_001439276.1		c.1342C>G	p.Arg448Gly	missense	Exon 4 of 4	NP_001426205.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRIP1	ENST00000318948.7	TSL:2 MANE Select	c.1342C>G	p.Arg448Gly	missense	Exon 4 of 4	ENSP00000327213.4
	NRIP1	ENST00000400199.5	TSL:3	c.1342C>G	p.Arg448Gly	missense	Exon 3 of 3	ENSP00000383060.1
	NRIP1	ENST00000400202.5	TSL:5	c.1342C>G	p.Arg448Gly	missense	Exon 3 of 3	ENSP00000383063.1

Frequencies

GnomAD3 genomes AF: 0.0702 AC: 10665 AN: 152030 Hom.: 501 Cov.: 32

Gnomad AFR AF: 0.0193

Gnomad AMI AF: 0.0736

Gnomad AMR AF: 0.0483

Gnomad ASJ AF: 0.0971

Gnomad EAS AF: 0.00212

Gnomad SAS AF: 0.0668

Gnomad FIN AF: 0.0977

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.106

Gnomad OTH AF: 0.0733

GnomAD2 exomes AF: 0.0793 AC: 19926 AN: 251244 AF XY: 0.0815

Gnomad AFR exome AF: 0.0158

Gnomad AMR exome AF: 0.0368

Gnomad ASJ exome AF: 0.115

Gnomad EAS exome AF: 0.00109

Gnomad FIN exome AF: 0.103

Gnomad NFE exome AF: 0.107

Gnomad OTH exome AF: 0.0848

GnomAD4 exome AF: 0.0949 AC: 138778 AN: 1461758 Hom.: 7027 Cov.: 35 AF XY: 0.0947 AC XY: 68844 AN XY: 727192

African (AFR) AF: 0.0142 AC: 474 AN: 33480

American (AMR) AF: 0.0388 AC: 1734 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.114 AC: 2977 AN: 26128

East Asian (EAS) AF: 0.000806 AC: 32 AN: 39690

South Asian (SAS) AF: 0.0778 AC: 6710 AN: 86250

European-Finnish (FIN) AF: 0.106 AC: 5676 AN: 53420

Middle Eastern (MID) AF: 0.0588 AC: 339 AN: 5768

European-Non Finnish (NFE) AF: 0.104 AC: 115749 AN: 1111908

Other (OTH) AF: 0.0842 AC: 5087 AN: 60392

GnomAD4 genome AF: 0.0701 AC: 10661 AN: 152148 Hom.: 501 Cov.: 32 AF XY: 0.0669 AC XY: 4980 AN XY: 74384

African (AFR) AF: 0.0192 AC: 798 AN: 41510

American (AMR) AF: 0.0482 AC: 737 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0971 AC: 337 AN: 3470

East Asian (EAS) AF: 0.00212 AC: 11 AN: 5184

South Asian (SAS) AF: 0.0665 AC: 321 AN: 4830

European-Finnish (FIN) AF: 0.0977 AC: 1033 AN: 10568

Middle Eastern (MID) AF: 0.0850 AC: 25 AN: 294

European-Non Finnish (NFE) AF: 0.106 AC: 7179 AN: 67988

Other (OTH) AF: 0.0726 AC: 153 AN: 2108

Alfa AF: 0.0958 Hom.: 581

Bravo AF: 0.0636

TwinsUK AF: 0.116 AC: 430

ALSPAC AF: 0.102 AC: 393

ESP6500AA AF: 0.0179 AC: 79

ESP6500EA AF: 0.104 AC: 898

ExAC AF: 0.0805 AC: 9769

Asia WGS AF: 0.0340 AC: 116 AN: 3476

EpiCase AF: 0.101

EpiControl AF: 0.0986

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.62	T
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		1.9
PrimateAI	Uncertain	0.51	T
PROVEAN	Pathogenic	-6.5	D
REVEL	Benign	0.14
Sift	Uncertain	0.019	D
Sift4G	Uncertain	0.010	D
Polyphen		1.0	D
Vest4		0.27
MPC		0.19
ClinPred		0.020	T
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.71
gMVP		0.35
Mutation Taster		=97/3	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2229742; hg19: chr21-16339172; COSMIC: COSV59656860; COSMIC: COSV59656860;