7-108194169-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001037132.4(NRCAM):c.1633C>A(p.Pro545Thr) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P545A) has been classified as Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: NRCAM NM_001037132.4 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.70

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.774

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NRCAM	NM_001037132.4	c.1633C>A	p.Pro545Thr	missense_variant, splice_region_variant	17/33	ENST00000379028.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NRCAM	ENST00000379028.8	c.1633C>A	p.Pro545Thr	missense_variant, splice_region_variant	17/33	5	NM_001037132.4	P1
NRCAM	ENST00000379024.8	c.1576C>A	p.Pro526Thr	missense_variant, splice_region_variant	16/30	1
NRCAM	ENST00000351718.8	c.1615C>A	p.Pro539Thr	missense_variant, splice_region_variant	16/28	1
NRCAM	ENST00000413765.6	c.1633C>A	p.Pro545Thr	missense_variant, splice_region_variant	17/31	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 48

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D;.;.;.;.;D;.
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;.;D
M_CAP	Benign	0.031	D
MetaRNN	Pathogenic	0.77	D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Pathogenic	3.5	H;.;.;.;.;H;.
MutationTaster	Benign	1.2e-10	P;P;P;P;P;P
PrimateAI	Benign	0.48	T
PROVEAN	Pathogenic	-6.2	D;.;D;D;.;D;.
REVEL	Uncertain	0.47
Sift	Uncertain	0.0010	D;.;D;D;.;D;.
Sift4G	Uncertain	0.0030	D;D;D;D;D;D;D
Polyphen		0.88	P;.;P;.;.;P;.
Vest4		0.66
MutPred		0.55		Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);.;.;.;Gain of sheet (P = 0.0477);.;
MVP		0.71
MPC		0.36
ClinPred		0.98	D
GERP RS		4.8
Varity_R		0.81
gMVP		0.75

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: rs6958498; hg19: chr7-107834613;