chr21-14964754-G-C

Position:

• chr21-14964754-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003489.4(NRIP1):​c.3439C>G​(p.Leu1147Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NRIP1 NM_003489.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10744652).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NRIP1	NM_003489.4	c.3439C>G	p.Leu1147Val	missense_variant	4/4	ENST00000318948.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NRIP1	ENST00000318948.7	c.3439C>G	p.Leu1147Val	missense_variant	4/4	2	NM_003489.4	P1
NRIP1	ENST00000400199.5	c.3439C>G	p.Leu1147Val	missense_variant	3/3	3		P1
NRIP1	ENST00000400202.5	c.3439C>G	p.Leu1147Val	missense_variant	3/3	5		P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Congenital anomalies of kidney and urinary tract 3 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

May 20, 2023

The observed missense c.3439C>G(p.Leu1147Val) variant in NRIP1 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is absent in gnomAD Exomes. The amino acid Leu at position 1147 is changed to a Val changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Leu1147Val in NRIP1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. Computational evidence (Polyphen - Benign, SIFT - Tolerated, and MutationTaster - Disease causing) predicts conflicting evidence on protein structure and function for this variant. For these reasons, this variant has been classified as Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.18	T;T;T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.68	T;.;.
M_CAP	Benign	0.0049	T
MetaRNN	Benign	0.11	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.4	M;M;M
MutationTaster	Benign	0.85	D;D;D
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-2.1	N;N;N
REVEL	Benign	0.029
Sift	Uncertain	0.011	D;D;D
Sift4G	Uncertain	0.023	D;D;D
Polyphen		0.012	B;B;B
Vest4		0.14
MutPred		0.34		Gain of sheet (P = 0.0125);Gain of sheet (P = 0.0125);Gain of sheet (P = 0.0125);
MVP		0.17
MPC		0.022
ClinPred		0.78	D
GERP RS		0.65
Varity_R		0.12
gMVP		0.26

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr21-16337075; COSMIC: COSV59658764; COSMIC: COSV59658764;