7-108194169-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001037132.4(NRCAM):c.1633C>G(p.Pro545Ala) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.766 in 1,612,338 control chromosomes in the GnomAD database, including 477,553 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.71 (39332 hom., cov: 33)
  • Exomes 𝑓: 0.77 (438221 hom.)
• Consequence: NRCAM NM_001037132.4 missense, splice_region
• Clinical Significance: Benign criteria provided, single submitter B:1
• 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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=3.1271684E-6).
• BP6: Variant 7-108194169-G-C is Benign according to our data. Variant chr7-108194169-G-C is described in ClinVar as [Benign]. Clinvar id is 1250798.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.858 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NRCAM	NM_001037132.4	c.1633C>G	p.Pro545Ala	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>G	p.Pro545Ala	missense_variant, splice_region_variant	17/33	5	NM_001037132.4	P1
NRCAM	ENST00000379024.8	c.1576C>G	p.Pro526Ala	missense_variant, splice_region_variant	16/30	1
NRCAM	ENST00000351718.8	c.1615C>G	p.Pro539Ala	missense_variant, splice_region_variant	16/28	1
NRCAM	ENST00000413765.6	c.1633C>G	p.Pro545Ala	missense_variant, splice_region_variant	17/31	2

Frequencies

GnomAD3 genomes AF: 0.707 AC: 107532 AN: 151996 Hom.: 39325 Cov.: 33

Gnomad AFR AF: 0.500

Gnomad AMI AF: 0.853

Gnomad AMR AF: 0.807

Gnomad ASJ AF: 0.760

Gnomad EAS AF: 0.879

Gnomad SAS AF: 0.698

Gnomad FIN AF: 0.785

Gnomad MID AF: 0.693

Gnomad NFE AF: 0.782

Gnomad OTH AF: 0.727

GnomAD3 exomes AF: 0.768 AC: 192941 AN: 251268 Hom.: 75174 AF XY: 0.766 AC XY: 103977 AN XY: 135798

Gnomad AFR exome AF: 0.493

Gnomad AMR exome AF: 0.856

Gnomad ASJ exome AF: 0.750

Gnomad EAS exome AF: 0.882

Gnomad SAS exome AF: 0.700

Gnomad FIN exome AF: 0.785

Gnomad NFE exome AF: 0.778

Gnomad OTH exome AF: 0.779

GnomAD4 exome AF: 0.772 AC: 1127959 AN: 1460224 Hom.: 438221 Cov.: 48 AF XY: 0.770 AC XY: 559601 AN XY: 726482

Gnomad4 AFR exome AF: 0.486

Gnomad4 AMR exome AF: 0.849

Gnomad4 ASJ exome AF: 0.757

Gnomad4 EAS exome AF: 0.872

Gnomad4 SAS exome AF: 0.704

Gnomad4 FIN exome AF: 0.784

Gnomad4 NFE exome AF: 0.781

Gnomad4 OTH exome AF: 0.762

GnomAD4 genome AF: 0.707 AC: 107579 AN: 152114 Hom.: 39332 Cov.: 33 AF XY: 0.712 AC XY: 52963 AN XY: 74358

Gnomad4 AFR AF: 0.500

Gnomad4 AMR AF: 0.807

Gnomad4 ASJ AF: 0.760

Gnomad4 EAS AF: 0.879

Gnomad4 SAS AF: 0.698

Gnomad4 FIN AF: 0.785

Gnomad4 NFE AF: 0.782

Gnomad4 OTH AF: 0.726

Alfa AF: 0.769 Hom.: 31079

Bravo AF: 0.703

TwinsUK AF: 0.785 AC: 2910

ALSPAC AF: 0.781 AC: 3011

ESP6500AA AF: 0.507 AC: 2232

ESP6500EA AF: 0.780 AC: 6706

ExAC AF: 0.756 AC: 91797

Asia WGS AF: 0.747 AC: 2596 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 08, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.44
Cadd	Uncertain	24
Dann	Benign	0.96
DEOGEN2	Uncertain	0.77	D;.;.;.;.;D;.
Eigen	Benign	0.026
Eigen_PC	Benign	0.20
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.82	T;T;T;T;T;.;T
MetaRNN	Benign	0.0000031	T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L;.;.;.;.;L;.
MutationTaster	Benign	1.9e-10	P;P;P;P;P;P
PrimateAI	Benign	0.45	T
PROVEAN	Pathogenic	-5.6	D;.;D;D;.;D;.
REVEL	Benign	0.17
Sift	Benign	0.24	T;.;T;T;.;T;.
Sift4G	Benign	0.48	T;T;T;T;T;T;T
Polyphen		0.0030	B;.;B;.;.;B;.
Vest4		0.064
MPC		0.23
ClinPred		0.11	T
GERP RS		4.8
Varity_R		0.25
gMVP		0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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; COSMIC: COSV61033740; COSMIC: COSV61033740;