Genetic Variant NM_003489.4:c.3465A>T (chr21-14964728-T-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_003489.4(NRIP1):c.3465A>T(p.Lys1155Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000072 in 1,389,830 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

NRIP1
NM_003489.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.263

Variant links:

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]

NRIP1 links:

ENSG00000235609 (HGNC:):

ENSG00000235609 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NRIP1	NM_003489.4 link	c.3465A>T	p.Lys1155Asn	missense_variant	Exon 4 of 4	ENST00000318948.7	NP_003480.2	P48552A8K171

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NRIP1	ENST00000318948.7 link	c.3465A>T	p.Lys1155Asn	missense_variant	Exon 4 of 4	2	NM_003489.4	ENSP00000327213.4	P48552
NRIP1	ENST00000400199.5 link	c.3465A>T	p.Lys1155Asn	missense_variant	Exon 3 of 3	3		ENSP00000383060.1	P48552
NRIP1	ENST00000400202.5 link	c.3465A>T	p.Lys1155Asn	missense_variant	Exon 3 of 3	5		ENSP00000383063.1	P48552
ENSG00000235609	ENST00000432230.6 link	n.87+49616A>T		intron_variant	Intron 1 of 3	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.20e-7

AC:

AN:

1389830

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

686252

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000254

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Jun 05, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3465A>T (p.K1155N) alteration is located in exon 4 (coding exon 1) of the NRIP1 gene. This alteration results from a A to T substitution at nucleotide position 3465, causing the lysine (K) at amino acid position 1155 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.82

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.44

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.23

T;T;T

Eigen

Benign

-0.13

Eigen_PC

Benign

-0.31

FATHMM_MKL

Benign

0.73

LIST_S2

Benign

0.81

T;.;.

M_CAP

Benign

0.0098

MetaRNN

Uncertain

0.43

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.5

M;M;M

PrimateAI

Uncertain

0.64

PROVEAN

Uncertain

-3.6

D;D;D

REVEL

Benign

0.24

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;D;D

Vest4

0.51

MutPred

0.45

Loss of ubiquitination at K1155 (P = 0.0077);Loss of ubiquitination at K1155 (P = 0.0077);Loss of ubiquitination at K1155 (P = 0.0077);

MVP

0.39

MPC

0.094

ClinPred

0.99

GERP RS

-7.0

Varity_R

0.80

gMVP

0.58

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over