chr7-108150049-C-T

Variant names:

• chr7-108150049-C-T
• NM_001037132.4:c.3776G>A

Variant summary

Our verdict is Uncertain significance. The variant received 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. Variant has been reported in ClinVar as Uncertain significance (★).

• 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
• Publications: 0 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001037132.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRCAM	NM_001037132.4	MANE Select	c.3776G>A	p.Gly1259Glu	missense	Exon 33 of 33	NP_001032209.1	Q92823-1
	NRCAM	NM_001371156.1		c.3785G>A	p.Gly1262Glu	missense	Exon 33 of 33	NP_001358085.1
	NRCAM	NM_001371131.1		c.3776G>A	p.Gly1259Glu	missense	Exon 34 of 34	NP_001358060.1	Q92823-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRCAM	ENST00000379028.8	TSL:5 MANE Select	c.3776G>A	p.Gly1259Glu	missense	Exon 33 of 33	ENSP00000368314.3	Q92823-1
	NRCAM	ENST00000379024.8	TSL:1	c.3440G>A	p.Gly1147Glu	missense	Exon 30 of 30	ENSP00000368310.4	Q92823-6
	NRCAM	ENST00000351718.8	TSL:1	c.3413G>A	p.Gly1138Glu	missense	Exon 28 of 28	ENSP00000325269.6	Q92823-4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.096	D
MetaRNN	Uncertain	0.69	D
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		7.9
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-7.3	D
REVEL	Pathogenic	0.69
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.59
MutPred		0.42		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
Mutation Taster		=54/46	polymorphism

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

Other links and lift over

hg19: chr7-107790494;