7-108240168-A-G

Variant names:

• chr7-108240168-A-G
• rs1269634
• NM_001037132.4:c.-104T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001037132.4(NRCAM):​c.-104T>C variant causes a splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.467 in 705,728 control chromosomes in the GnomAD database, including 84,132 homozygotes. In-silico tool predicts a benign 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.

• Frequency:
  • Genomes: 𝑓 0.40 (14409 hom., cov: 32)
  • Exomes 𝑓: 0.49 (69723 hom.)
• Consequence: NRCAM NM_001037132.4 splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.105
• Publications: 14 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.807 is higher than 0.05.

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.-104T>C		splice_region	Exon 4 of 33	NP_001032209.1	Q92823-1
	NRCAM	NM_001037132.4	MANE Select	c.-104T>C		5_prime_UTR	Exon 4 of 33	NP_001032209.1	Q92823-1
	NRCAM	NM_001371156.1		c.-104T>C		splice_region	Exon 4 of 33	NP_001358085.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRCAM	ENST00000379028.8	TSL:5 MANE Select	c.-104T>C		splice_region	Exon 4 of 33	ENSP00000368314.3	Q92823-1
	NRCAM	ENST00000379024.8	TSL:1	c.-104T>C		splice_region	Exon 4 of 30	ENSP00000368310.4	Q92823-6
	NRCAM	ENST00000351718.8	TSL:1	c.-104T>C		splice_region	Exon 4 of 28	ENSP00000325269.6	Q92823-4

Frequencies

GnomAD3 genomes AF: 0.397 AC: 60344 AN: 151956 Hom.: 14416 Cov.: 32

Gnomad AFR AF: 0.142

Gnomad AMI AF: 0.644

Gnomad AMR AF: 0.545

Gnomad ASJ AF: 0.550

Gnomad EAS AF: 0.828

Gnomad SAS AF: 0.495

Gnomad FIN AF: 0.423

Gnomad MID AF: 0.516

Gnomad NFE AF: 0.463

Gnomad OTH AF: 0.421

GnomAD4 exome AF: 0.486 AC: 269039 AN: 553652 Hom.: 69723 Cov.: 7 AF XY: 0.486 AC XY: 143832 AN XY: 296094

African (AFR) AF: 0.139 AC: 2085 AN: 14970

American (AMR) AF: 0.632 AC: 16448 AN: 26036

Ashkenazi Jewish (ASJ) AF: 0.538 AC: 8575 AN: 15928

East Asian (EAS) AF: 0.830 AC: 28236 AN: 34006

South Asian (SAS) AF: 0.491 AC: 26120 AN: 53234

European-Finnish (FIN) AF: 0.436 AC: 18036 AN: 41404

Middle Eastern (MID) AF: 0.470 AC: 1067 AN: 2270

European-Non Finnish (NFE) AF: 0.460 AC: 154787 AN: 336626

Other (OTH) AF: 0.469 AC: 13685 AN: 29178

GnomAD4 genome AF: 0.397 AC: 60339 AN: 152076 Hom.: 14409 Cov.: 32 AF XY: 0.404 AC XY: 30035 AN XY: 74332

African (AFR) AF: 0.142 AC: 5881 AN: 41522

American (AMR) AF: 0.545 AC: 8327 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.550 AC: 1907 AN: 3470

East Asian (EAS) AF: 0.828 AC: 4280 AN: 5168

South Asian (SAS) AF: 0.494 AC: 2381 AN: 4818

European-Finnish (FIN) AF: 0.423 AC: 4462 AN: 10554

Middle Eastern (MID) AF: 0.497 AC: 146 AN: 294

European-Non Finnish (NFE) AF: 0.463 AC: 31479 AN: 67956

Other (OTH) AF: 0.422 AC: 889 AN: 2108

Alfa AF: 0.445 Hom.: 44177

Bravo AF: 0.398

Asia WGS AF: 0.587 AC: 2038 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	8.3
DANN	Benign	0.65
PhyloP100		-0.10
Mutation Taster		=300/0	polymorphism (auto)

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: rs1269634; hg19: chr7-107880612; COSMIC: COSV61034793; COSMIC: COSV61034793;