7-108150049-C-T

Position:

• chr7-108150049-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001037132.4(NRCAM):​c.3776G>A​(p.Gly1259Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: NRCAM NM_001037132.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.91

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NRCAM	NM_001037132.4	c.3776G>A	p.Gly1259Glu	missense_variant	33/33	ENST00000379028.8	NP_001032209.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NRCAM	ENST00000379028.8	c.3776G>A	p.Gly1259Glu	missense_variant	33/33	5	NM_001037132.4	ENSP00000368314.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 04, 2024

The c.3776G>A (p.G1259E) alteration is located in exon 30 (coding exon 30) of the NRCAM gene. This alteration results from a G to A substitution at nucleotide position 3776, causing the glycine (G) at amino acid position 1259 to be replaced by a glutamic acid (E). 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	0.33
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D;.;.;.;.;D
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;.
M_CAP	Uncertain	0.096	D
MetaRNN	Uncertain	0.69	D;D;D;D;D;D
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Uncertain	2.1	M;.;.;.;.;M
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-7.3	D;.;D;D;.;D
REVEL	Pathogenic	0.69
Sift	Pathogenic	0.0	D;.;D;D;.;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D
Polyphen		1.0	D;.;D;.;.;D
Vest4		0.59
MutPred		0.42		Gain of solvent accessibility (P = 0.0411);.;.;.;.;Gain of solvent accessibility (P = 0.0411);
MVP		0.98
MPC		1.0
ClinPred		1.0	D
GERP RS		6.2
Varity_R		0.92
gMVP		0.50

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-107790494;