21-14964781-T-C

Variant summary

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

The NM_003489.4(NRIP1):c.3412A>G(p.Ser1138Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00052 in 1,598,780 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S1138S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0029 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00027 (1 hom.)
• Consequence: NRIP1 NM_003489.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 1.78

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=0.0051377416).
• BP6: Variant 21-14964781-T-C is Benign according to our data. Variant chr21-14964781-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 769116.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=1, Uncertain_significance=1}.
• BS2: High AC in GnomAd at 444 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NRIP1	NM_003489.4	c.3412A>G	p.Ser1138Gly	missense_variant	4/4	ENST00000318948.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NRIP1	ENST00000318948.7	c.3412A>G	p.Ser1138Gly	missense_variant	4/4	2	NM_003489.4	P1
NRIP1	ENST00000400199.5	c.3412A>G	p.Ser1138Gly	missense_variant	3/3	3		P1
NRIP1	ENST00000400202.5	c.3412A>G	p.Ser1138Gly	missense_variant	3/3	5		P1

Frequencies

GnomAD3 genomes AF: 0.00292 AC: 444 AN: 152186 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0103

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000721

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000805 AC: 190 AN: 236110 Hom.: 2 AF XY: 0.000650 AC XY: 83 AN XY: 127604

Gnomad AFR exome AF: 0.0108

Gnomad AMR exome AF: 0.000453

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000367

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000184

Gnomad OTH exome AF: 0.000178

GnomAD4 exome AF: 0.000270 AC: 390 AN: 1446476 Hom.: 1 Cov.: 32 AF XY: 0.000246 AC XY: 177 AN XY: 719332

Gnomad4 AFR exome AF: 0.0102

Gnomad4 AMR exome AF: 0.000495

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000361

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000451

Gnomad4 OTH exome AF: 0.000570

GnomAD4 genome AF: 0.00290 AC: 442 AN: 152304 Hom.: 2 Cov.: 32 AF XY: 0.00303 AC XY: 226 AN XY: 74498

Gnomad4 AFR AF: 0.0103

Gnomad4 AMR AF: 0.000720

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000524 Hom.: 1

Bravo AF: 0.00320

ESP6500AA AF: 0.00999 AC: 44

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00102 AC: 124

Asia WGS AF: 0.000289 AC: 1 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.3412A>G (p.S1138G) alteration is located in exon 4 (coding exon 1) of the NRIP1 gene. This alteration results from a A to G substitution at nucleotide position 3412, causing the serine (S) at amino acid position 1138 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

NRIP1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 11, 2021

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). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Oct 03, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.74
Cadd	Benign	14
Dann	Benign	0.97
DEOGEN2	Benign	0.065	T;T;T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.58	T;.;.
MetaRNN	Benign	0.0051	T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.7	L;L;L
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.1	N;N;N
REVEL	Benign	0.027
Sift	Benign	0.21	T;T;T
Sift4G	Benign	0.39	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.051
MVP		0.28
MPC		0.024
ClinPred		0.0035	T
GERP RS		1.9
Varity_R		0.058
gMVP		0.14

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: rs140307100; hg19: chr21-16337102;