7-108149972-C-T

Variant names:

• chr7-108149972-C-T
• rs74708699
• NM_001037132.4:c.3853G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001037132.4(NRCAM):​c.3853G>A​(p.Ala1285Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00137 in 1,613,966 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0073 (17 hom., cov: 33)
  • Exomes 𝑓: 0.00075 (9 hom.)
• Consequence: NRCAM NM_001037132.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 5.20
• Publications: 10 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003005296).
• BP6: Variant 7-108149972-C-T is Benign according to our data. Variant chr7-108149972-C-T is described in ClinVar as Benign. ClinVar VariationId is 714356.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00732 (1115/152294) while in subpopulation AFR AF = 0.0254 (1054/41558). AF 95% confidence interval is 0.0241. There are 17 homozygotes in GnomAd4. There are 507 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 17 AR gene

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.3853G>A	p.Ala1285Thr	missense	Exon 33 of 33	NP_001032209.1	Q92823-1
	NRCAM	NM_001371156.1		c.3862G>A	p.Ala1288Thr	missense	Exon 33 of 33	NP_001358085.1
	NRCAM	NM_001371131.1		c.3853G>A	p.Ala1285Thr	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.3853G>A	p.Ala1285Thr	missense	Exon 33 of 33	ENSP00000368314.3	Q92823-1
	NRCAM	ENST00000379024.8	TSL:1	c.3517G>A	p.Ala1173Thr	missense	Exon 30 of 30	ENSP00000368310.4	Q92823-6
	NRCAM	ENST00000351718.8	TSL:1	c.3490G>A	p.Ala1164Thr	missense	Exon 28 of 28	ENSP00000325269.6	Q92823-4

Frequencies

GnomAD3 genomes AF: 0.00731 AC: 1112 AN: 152178 Hom.: 17 Cov.: 33

Gnomad AFR AF: 0.0254

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00308

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00479

GnomAD2 exomes AF: 0.00184 AC: 462 AN: 250866 AF XY: 0.00142

Gnomad AFR exome AF: 0.0246

Gnomad AMR exome AF: 0.00122

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000124

Gnomad OTH exome AF: 0.000654

GnomAD4 exome AF: 0.000745 AC: 1089 AN: 1461672 Hom.: 9 Cov.: 31 AF XY: 0.000633 AC XY: 460 AN XY: 727118

African (AFR) AF: 0.0253 AC: 846 AN: 33466

American (AMR) AF: 0.00143 AC: 64 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86220

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00121 AC: 7 AN: 5766

European-Non Finnish (NFE) AF: 0.0000710 AC: 79 AN: 1111912

Other (OTH) AF: 0.00147 AC: 89 AN: 60392

GnomAD4 genome AF: 0.00732 AC: 1115 AN: 152294 Hom.: 17 Cov.: 33 AF XY: 0.00681 AC XY: 507 AN XY: 74462

African (AFR) AF: 0.0254 AC: 1054 AN: 41558

American (AMR) AF: 0.00308 AC: 47 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68030

Other (OTH) AF: 0.00474 AC: 10 AN: 2110

Alfa AF: 0.00271 Hom.: 9

Bravo AF: 0.00852

ESP6500AA AF: 0.0261 AC: 115

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00239 AC: 290

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000356

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	NRCAM-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.42
CADD	Uncertain	24
DANN	Benign	0.96
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.014
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.86	D
MetaRNN	Benign	0.0030	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N
PhyloP100		5.2
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.71	N
REVEL	Benign	0.050
Sift	Benign	0.72	T
Sift4G	Benign	0.85	T
Polyphen		0.0010	B
Vest4		0.12
MVP		0.71
MPC		0.23
ClinPred		0.018	T
GERP RS		5.3
Varity_R		0.030
gMVP		0.21
Mutation Taster		=93/7	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

dbSNP: rs74708699; hg19: chr7-107790417; COSMIC: COSV99065355; COSMIC: COSV99065355;