chr7-108168331-C-T

Position:

• chr7-108168331-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001037132.4(NRCAM):​c.3259G>A​(p.Glu1087Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000472 in 1,609,912 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00032 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00049 (2 hom.)
• Consequence: NRCAM NM_001037132.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.907

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]

LOC102724363 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.050746173).
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NRCAM	NM_001037132.4	c.3259G>A	p.Glu1087Lys	missense_variant	29/33	ENST00000379028.8
LOC102724363	XR_002956579.2	n.202-350C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NRCAM	ENST00000379028.8	c.3259G>A	p.Glu1087Lys	missense_variant	29/33	5	NM_001037132.4	P1

Frequencies

GnomAD3 genomes AF: 0.000322 AC: 49 AN: 152146 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000573

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000321 AC: 79 AN: 245816 Hom.: 1 AF XY: 0.000367 AC XY: 49 AN XY: 133422

Gnomad AFR exome AF: 0.000130

Gnomad AMR exome AF: 0.000181

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000401

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000481

Gnomad OTH exome AF: 0.000849

GnomAD4 exome AF: 0.000488 AC: 711 AN: 1457648 Hom.: 2 Cov.: 30 AF XY: 0.000490 AC XY: 355 AN XY: 724974

Gnomad4 AFR exome AF: 0.000150

Gnomad4 AMR exome AF: 0.000159

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000422

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000568

Gnomad4 OTH exome AF: 0.000432

GnomAD4 genome AF: 0.000322 AC: 49 AN: 152264 Hom.: 0 Cov.: 33 AF XY: 0.000282 AC XY: 21 AN XY: 74454

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000573

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000555 Hom.: 0

Bravo AF: 0.000261

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000485 AC: 4

ExAC AF: 0.000364 AC: 44

EpiCase AF: 0.000824

EpiControl AF: 0.00102

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 03, 2022

The c.3259G>A (p.E1087K) alteration is located in exon 26 (coding exon 26) of the NRCAM gene. This alteration results from a G to A substitution at nucleotide position 3259, causing the glutamic acid (E) at amino acid position 1087 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	20
DANN	Benign	0.93
DEOGEN2	Benign	0.16	T;.;T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.34
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.88	D;D;.
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.051	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L;.;L
MutationTaster	Benign	0.98	D;D;D;D;D;D
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.82	N;.;N
REVEL	Benign	0.088
Sift	Benign	0.63	T;.;T
Sift4G	Benign	0.88	T;T;T
Polyphen		0.030	B;.;B
Vest4		0.18
MVP		0.61
MPC		0.27
ClinPred		0.020	T
GERP RS		1.8
Varity_R		0.056
gMVP		0.57

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: rs182113726; hg19: chr7-107808776;