chr3-173605041-A-G

Position:

• chr3-173605041-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001365925.2(NLGN1):​c.443A>G​(p.Asp148Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NLGN1 NM_001365925.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.95

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), NLGN1. . Gene score misZ 2.2182 (greater than the threshold 3.09). Trascript score misZ 3.3825 (greater than threshold 3.09). GenCC has associacion of gene with autism, susceptibility to, 20.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NLGN1	NM_001365925.2	c.443A>G	p.Asp148Gly	missense_variant	2/7	ENST00000695368.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NLGN1	ENST00000695368.1	c.443A>G	p.Asp148Gly	missense_variant	2/7		NM_001365925.2	A1
NLGN1	ENST00000415045.2	c.443A>G	p.Asp148Gly	missense_variant	2/8	1
NLGN1	ENST00000361589.8	c.443A>G	p.Asp148Gly	missense_variant	2/6	1		P2
NLGN1	ENST00000457714.5	c.443A>G	p.Asp148Gly	missense_variant	3/7	1		P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Mar 01, 2023

The c.443A>G (p.D148G) alteration is located in exon 3 (coding exon 1) of the NLGN1 gene. This alteration results from a A to G substitution at nucleotide position 443, causing the aspartic acid (D) at amino acid position 148 to be replaced by a glycine (G). 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	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	.;.;T
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	.;D;D
M_CAP	Benign	0.049	D
MetaRNN	Uncertain	0.64	D;D;D
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	0.17	N;N;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-3.5	D;D;D
REVEL	Uncertain	0.40
Sift	Benign	0.046	D;D;D
Sift4G	Benign	0.076	T;T;T
Polyphen		0.19	B;B;.
Vest4		0.54
MutPred		0.53		Loss of disorder (P = 0.1854);Loss of disorder (P = 0.1854);Loss of disorder (P = 0.1854);
MVP		0.75
MPC		1.3
ClinPred		0.97	D
GERP RS		5.6
gMVP		0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-173322831;