6-11185553-C-A

Variant names:

• chr6-11185553-C-A
• rs142392451
• NM_006403.4:c.2114G>T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_006403.4(NEDD9):​c.2114G>T​(p.Arg705Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000041 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: NEDD9 NM_006403.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.77

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]

ENSG00000247925 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEDD9	NM_006403.4	c.2114G>T	p.Arg705Leu	missense_variant	Exon 7 of 7	ENST00000379446.10	NP_006394.1
NEDD9	NM_001142393.2	c.2114G>T	p.Arg705Leu	missense_variant	Exon 8 of 8		NP_001135865.1
NEDD9	NM_001271033.2	c.1667G>T	p.Arg556Leu	missense_variant	Exon 6 of 6		NP_001257962.1
NEDD9	NR_073131.1	n.2721G>T		non_coding_transcript_exon_variant	Exon 10 of 10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEDD9	ENST00000379446.10	c.2114G>T	p.Arg705Leu	missense_variant	Exon 7 of 7	1	NM_006403.4	ENSP00000368759.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461894 Hom.: 0 Cov.: 37 AF XY: 0.00000550 AC XY: 4 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000282 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 26, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2114G>T (p.R705L) alteration is located in exon 8 (coding exon 7) of the NEDD9 gene. This alteration results from a G to T substitution at nucleotide position 2114, causing the arginine (R) at amino acid position 705 to be replaced by a leucine (L). 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	Benign	0.25
BayesDel_addAF	Benign	0.011	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	T;T;.
Eigen	Uncertain	0.21
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Benign	0.035	D
MetaRNN	Uncertain	0.54	D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L;.;L
PrimateAI	Benign	0.46	T
PROVEAN	Pathogenic	-4.5	D;.;D
REVEL	Benign	0.17
Sift	Uncertain	0.0010	D;.;D
Sift4G	Uncertain	0.021	D;D;D
Polyphen		0.89	P;.;.
Vest4		0.52
MutPred		0.40		Loss of disorder (P = 0.0879);.;Loss of disorder (P = 0.0879);
MVP		0.57
MPC		0.69
ClinPred		0.98	D
GERP RS		6.0
Varity_R		0.56
gMVP		0.51

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: rs142392451; hg19: chr6-11185786;