chr7-108168324-T-G

Position:

• chr7-108168324-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001037132.4(NRCAM):​c.3266A>C​(p.Glu1089Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. 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: 2.49

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]

LOC102724363 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20957857).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NRCAM	NM_001037132.4	c.3266A>C	p.Glu1089Ala	missense_variant	29/33	ENST00000379028.8
LOC102724363	XR_002956579.2	n.202-357T>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NRCAM	ENST00000379028.8	c.3266A>C	p.Glu1089Ala	missense_variant	29/33	5	NM_001037132.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

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

Jul 26, 2022

The c.3266A>C (p.E1089A) alteration is located in exon 26 (coding exon 26) of the NRCAM gene. This alteration results from a A to C substitution at nucleotide position 3266, causing the glutamic acid (E) at amino acid position 1089 to be replaced by an alanine (A). 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	0.21
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Uncertain	23
DANN	Benign	0.93
DEOGEN2	Benign	0.21	T;.;T
Eigen	Benign	-0.15
Eigen_PC	Benign	0.018
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	D;D;.
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.21	T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.8	L;.;L
MutationTaster	Benign	0.97	D;D;D;D;D;D
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.3	N;.;N
REVEL	Benign	0.077
Sift	Benign	0.60	T;.;T
Sift4G	Benign	0.68	T;T;T
Polyphen		0.0010	B;.;B
Vest4		0.28
MutPred		0.53		Loss of sheet (P = 0.0457);.;Loss of sheet (P = 0.0457);
MVP		0.74
MPC		0.28
ClinPred		0.41	T
GERP RS		4.7
Varity_R		0.13
gMVP		0.36

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: rs1585961253; hg19: chr7-107808769;