7-108150041-C-A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_001037132.4(NRCAM):c.3784G>T(p.Val1262Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,764 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

NRCAM
NM_001037132.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.91

Publications

0 publications found

Variant links:

Genes affected

NRCAM (HGNC:7994): (neuronal cell adhesion molecule) Cell adhesion molecules (CAMs) are members of the immunoglobulin superfamily. This gene encodes a neuronal cell adhesion molecule with multiple immunoglobulin-like C2-type domains and fibronectin type-III domains. This ankyrin-binding protein is involved in neuron-neuron adhesion and promotes directional signaling during axonal cone growth. This gene is also expressed in non-neural tissues and may play a general role in cell-cell communication via signaling from its intracellular domain to the actin cytoskeleton during directional cell migration. Allelic variants of this gene have been associated with autism and addiction vulnerability. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

NRCAM Gene-Disease associations (from GenCC):

neurodevelopmental disorder with neuromuscular and skeletal abnormalities
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics

NRCAM links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.389019).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NRCAM	NM_001037132.4 link	c.3784G>T	p.Val1262Phe	missense_variant	Exon 33 of 33	ENST00000379028.8	NP_001032209.1	Q92823-1Q14CA1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NRCAM	ENST00000379028.8 link	c.3784G>T	p.Val1262Phe	missense_variant	Exon 33 of 33	5	NM_001037132.4	ENSP00000368314.3		Q92823-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000796

AC:

AN:

251128

AF XY:

0.00000737

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461764

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727174

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33474

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111910

Other (OTH)

AF:

0.00

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000468

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Jul 05, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.3784G>T (p.V1262F) alteration is located in exon 30 (coding exon 30) of the NRCAM gene. This alteration results from a G to T substitution at nucleotide position 3784, causing the valine (V) at amino acid position 1262 to be replaced by a phenylalanine (F). 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

0.19

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Uncertain

0.030

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.75

D;.;.;.;.;D

Eigen

Pathogenic

0.73

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.96

D;D;D;D;D;.

M_CAP

Benign

0.059

MetaRNN

Benign

0.39

T;T;T;T;T;T

MetaSVM

Uncertain

0.49

MutationAssessor

Benign

1.4

L;.;.;.;.;L

PhyloP100

7.9

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

-1.9

N;.;N;N;.;N

REVEL

Uncertain

0.42

Sift

Uncertain

0.024

D;.;D;D;.;D

Sift4G

Uncertain

0.041

D;D;D;D;D;D

Polyphen

1.0

D;.;D;.;.;D

Vest4

0.31

MutPred

0.29

Gain of sheet (P = 0.0221);.;.;.;.;Gain of sheet (P = 0.0221);

MVP

0.96

MPC

1.0

ClinPred

0.75

GERP RS

6.2

Varity_R

0.25

gMVP

0.22

Mutation Taster

=65/35

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over