chr7-108149972-C-T

Position:

• chr7-108149972-C-T

Variant summary

Our verdict is Benign. Variant got -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. 12/20 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:2
• Conservation: PhyloP100: 5.20

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 -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 id 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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NRCAM	NM_001037132.4	c.3853G>A	p.Ala1285Thr	missense_variant	33/33	ENST00000379028.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NRCAM	ENST00000379028.8	c.3853G>A	p.Ala1285Thr	missense_variant	33/33	5	NM_001037132.4	P1

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

GnomAD3 exomes AF: 0.00184 AC: 462 AN: 250866 Hom.: 1 AF XY: 0.00142 AC XY: 193 AN XY: 135558

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 SAS exome AF: 0.0000654

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

Gnomad4 AFR exome AF: 0.0253

Gnomad4 AMR exome AF: 0.00143

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000710

Gnomad4 OTH exome AF: 0.00147

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

Gnomad4 AFR AF: 0.0254

Gnomad4 AMR AF: 0.00308

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00474

Alfa AF: 0.00131 Hom.: 4

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

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Apr 20, 2018

- -

NRCAM-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 31, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

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;.;.;.;.;T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.014
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.86	D;D;D;D;D;.
MetaRNN	Benign	0.0030	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N;.;.;.;.;N
MutationTaster	Benign	1.0	D;D;N;N;N
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.71	N;.;N;N;.;N
REVEL	Benign	0.050
Sift	Benign	0.72	T;.;T;T;.;T
Sift4G	Benign	0.85	T;T;T;T;T;T
Polyphen		0.0010	B;.;B;.;.;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

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