3-173604893-G-C

Variant names:

• chr3-173604893-G-C
• rs746042193
• NM_001365925.2:c.295G>C

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4

The NM_001365925.2(NLGN1):​c.295G>C​(p.Glu99Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 1,461,524 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: NLGN1 NM_001365925.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.60

Genes affected

NLGN1 (HGNC:14291): (neuroligin 1) This gene encodes a member of a family of neuronal cell surface proteins. Members of this family may act as splice site-specific ligands for beta-neurexins and may be involved in the formation and remodeling of central nervous system synapses. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.2695191).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NLGN1	NM_001365925.2	c.295G>C	p.Glu99Gln	missense_variant	Exon 2 of 7	ENST00000695368.1	NP_001352854.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NLGN1	ENST00000695368.1	c.295G>C	p.Glu99Gln	missense_variant	Exon 2 of 7		NM_001365925.2	ENSP00000511841.1
NLGN1	ENST00000415045.2	c.295G>C	p.Glu99Gln	missense_variant	Exon 2 of 8	1		ENSP00000410374.2
NLGN1	ENST00000361589.8	c.295G>C	p.Glu99Gln	missense_variant	Exon 2 of 6	1		ENSP00000354541.4
NLGN1	ENST00000457714.5	c.295G>C	p.Glu99Gln	missense_variant	Exon 3 of 7	1		ENSP00000392500.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 250926 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135618

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000654

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1461524 Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5 AN XY: 727076

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome Cov.: 32

Alfa AF: 0.000556 Hom.: 0

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Jun 02, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.295G>C (p.E99Q) alteration is located in exon 3 (coding exon 1) of the NLGN1 gene. This alteration results from a G to C substitution at nucleotide position 295, causing the glutamic acid (E) at amino acid position 99 to be replaced by a glutamine (Q). 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
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.33	.;.;T
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	.;D;D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.27	T;T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	-0.58	N;N;.
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.6	N;N;D
REVEL	Benign	0.26
Sift	Benign	0.15	T;T;T
Sift4G	Benign	0.47	T;T;T
Polyphen		0.62	P;P;.
Vest4		0.63
MutPred		0.40		Loss of glycosylation at P100 (P = 0.0072);Loss of glycosylation at P100 (P = 0.0072);Loss of glycosylation at P100 (P = 0.0072);
MVP		0.54
MPC		1.1
ClinPred		0.35	T
GERP RS		5.6
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: rs746042193; hg19: chr3-173322683;