Variant 3-111122207-A-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBS2_Supporting

The NM_015480.3(NECTIN3):c.886A>C(p.Asn296His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00282 in 1,612,538 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0020 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0029 ( 6 hom. )

Consequence

NECTIN3
NM_015480.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity no assertion criteria provided P:1B:1

Conservation

PhyloP100: 7.89

Variant links:

Genes affected

NECTIN3 (HGNC:17664): (nectin cell adhesion molecule 3) This gene encodes a member of the nectin family of proteins, which function as adhesion molecules at adherens junctions. This family member interacts with other nectin-like proteins and with afadin, a filamentous actin-binding protein involved in the regulation of directional motility, cell proliferation and survival. This gene plays a role in ocular development involving the ciliary body. Mutations in this gene are believed to result in congenital ocular defects. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2011]

NECTIN3 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.07085538).

BS2

High Homozygotes in GnomAd4 at 2 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NECTIN3	NM_015480.3 linkuse as main transcript	c.886A>C	p.Asn296His	missense_variant	4/6	ENST00000485303.6	NP_056295.1	Q9NQS3-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
NECTIN3	ENST00000485303.6 linkuse as main transcript	c.886A>C	p.Asn296His	missense_variant	4/6	1	NM_015480.3	ENSP00000418070.1	Q9NQS3-1
NECTIN3	ENST00000319792.7 linkuse as main transcript	c.886A>C	p.Asn296His	missense_variant	4/6	1		ENSP00000321514.3	Q9NQS3-2
NECTIN3	ENST00000493615.5 linkuse as main transcript	c.817A>C	p.Asn273His	missense_variant	4/9	2		ENSP00000420579.1	Q9NQS3-3
NECTIN3	ENST00000486596.5 linkuse as main transcript	c.586A>C	p.Asn196His	missense_variant	3/4	5		ENSP00000417572.1	H7C4L0

Frequencies

GnomAD3 genomes

AF:

0.00202

AC:

308

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000748

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00321

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.000471

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00307

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.00190

AC:

478

AN:

251076

Hom.:

AF XY:

0.00190

AC XY:

258

AN XY:

135716

show subpopulations

Gnomad AFR exome

AF:

0.000616

Gnomad AMR exome

AF:

0.00188

Gnomad ASJ exome

AF:

0.00268

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000458

Gnomad FIN exome

AF:

0.000601

Gnomad NFE exome

AF:

0.00288

Gnomad OTH exome

AF:

0.00359

GnomAD4 exome

AF:

0.00291

AC:

4247

AN:

1460252

Hom.:

Cov.:

AF XY:

0.00284

AC XY:

2062

AN XY:

726522

show subpopulations

Gnomad4 AFR exome

AF:

0.000508

Gnomad4 AMR exome

AF:

0.00197

Gnomad4 ASJ exome

AF:

0.00180

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000313

Gnomad4 FIN exome

AF:

0.000618

Gnomad4 NFE exome

AF:

0.00350

Gnomad4 OTH exome

AF:

0.00244

GnomAD4 genome

AF:

0.00202

AC:

308

AN:

152286

Hom.:

Cov.:

AF XY:

0.00187

AC XY:

139

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.000746

Gnomad4 AMR

AF:

0.00320

Gnomad4 ASJ

AF:

0.00288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.000471

Gnomad4 NFE

AF:

0.00307

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00275

Hom.:

Bravo

AF:

0.00223

TwinsUK

AF:

0.00297

AC:

ALSPAC

AF:

0.00363

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00419

AC:

ExAC

AF:

0.00180

AC:

218

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00284

EpiControl

AF:

0.00314

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Developmental cataract

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Department of Ophthalmology, Flinders University

Jul 29, 2016

- -

NECTIN3-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 16, 2024

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). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.48

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.29

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.49

T;.;.

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.89

D;D;D

M_CAP

Benign

0.030

MetaRNN

Benign

0.071

T;T;T

MetaSVM

Benign

-0.99

PrimateAI

Uncertain

0.58

PROVEAN

Uncertain

-4.2

D;D;D

REVEL

Uncertain

0.45

Sift

Pathogenic

0.0

D;D;D

Sift4G

Uncertain

0.0040

D;D;D

Polyphen

1.0

D;.;.

Vest4

0.78

MVP

0.76

MPC

0.78

ClinPred

0.032

GERP RS

5.7

Varity_R

0.82

gMVP

0.86

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over