Variant 6-11185374-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3_ModerateBS2

The NM_006403.4(NEDD9):c.2293C>T(p.Arg765Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000682 in 1,614,076 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

NEDD9
NM_006403.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.375

Variant links:

Genes affected

NEDD9 (HGNC:7733): (neural precursor cell expressed, developmentally down-regulated 9) The protein encoded by this gene is a member of the CRK-associated substrates family. Members of this family are adhesion docking molecules that mediate protein-protein interactions for signal transduction pathways. This protein is a focal adhesion protein that acts as a scaffold to regulate signaling complexes important in cell attachment, migration and invasion as well as apoptosis and the cell cycle. This protein has also been reported to have a role in cancer metastasis. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2012]

NEDD9 links:

NEDD9 (HGNC:):

NEDD9 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.899

BS2

High AC in GnomAdExome4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEDD9	NM_006403.4 linkuse as main transcript	c.2293C>T	p.Arg765Trp	missense_variant	7/7	ENST00000379446.10	NP_006394.1	Q14511-1
NEDD9	NM_001142393.2 linkuse as main transcript	c.2293C>T	p.Arg765Trp	missense_variant	8/8		NP_001135865.1	Q14511-3A0A024QZV9
NEDD9	NM_001271033.2 linkuse as main transcript	c.1846C>T	p.Arg616Trp	missense_variant	6/6		NP_001257962.1	Q14511A0A087WUD2
NEDD9	NR_073131.1 linkuse as main transcript	n.2900C>T		non_coding_transcript_exon_variant	10/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEDD9	ENST00000379446.10 linkuse as main transcript	c.2293C>T	p.Arg765Trp	missense_variant	7/7	1	NM_006403.4	ENSP00000368759.5		Q14511-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000616

AC:

AN:

1461894

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000719

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152182

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74342

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000329

Hom.:

Bravo

AF:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 16, 2024

The c.2293C>T (p.R765W) alteration is located in exon 8 (coding exon 7) of the NEDD9 gene. This alteration results from a C to T substitution at nucleotide position 2293, causing the arginine (R) at amino acid position 765 to be replaced by a tryptophan (W). 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

Pathogenic

0.20

BayesDel_noAF

Uncertain

0.050

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.43

T;T;.

Eigen

Benign

0.088

Eigen_PC

Benign

-0.019

FATHMM_MKL

Benign

0.38

LIST_S2

Pathogenic

0.99

D;D;D

M_CAP

Uncertain

0.13

MetaRNN

Pathogenic

0.90

D;D;D

MetaSVM

Benign

-0.81

MutationAssessor

Uncertain

2.7

M;.;M

PrimateAI

Uncertain

0.70

PROVEAN

Pathogenic

-6.1

D;.;D

REVEL

Uncertain

0.54

Sift

Pathogenic

0.0

D;.;D

Sift4G

Pathogenic

0.0010

D;D;D

Polyphen

1.0

D;.;.

Vest4

0.89

MutPred

0.75

Gain of catalytic residue at L763 (P = 0.0465);.;Gain of catalytic residue at L763 (P = 0.0465);

MVP

0.80

MPC

0.83

ClinPred

0.99

GERP RS

2.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.73

gMVP

0.62

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