chr1-107324724-C-T

Variant names:

• chr1-107324724-C-T
• rs386352339
• NM_001113226.3:c.689C>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001113226.3(NTNG1):​c.689C>T​(p.Ala230Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,336 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: NTNG1 NM_001113226.3 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 7.91

Genes affected

NTNG1 (HGNC:23319): (netrin G1) This gene encodes a preproprotein that is processed into a secreted protein containing eukaroytic growth factor (EGF)-like domains. This protein acts to guide axon growth during neuronal development. Polymorphisms in this gene may be associated with schizophrenia. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Aug 2015]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.798

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NTNG1	NM_001113226.3	c.689C>T	p.Ala230Val	missense_variant	Exon 3 of 8	ENST00000370068.6	NP_001106697.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NTNG1	ENST00000370068.6	c.689C>T	p.Ala230Val	missense_variant	Exon 3 of 8	5	NM_001113226.3	ENSP00000359085.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000400 AC: 1 AN: 249732 Hom.: 0 AF XY: 0.00000741 AC XY: 1 AN XY: 134936

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000291

Gnomad ASJ exome AF: 0.00

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: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461336 Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3 AN XY: 726982

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

not provided Uncertain:1

-

Richard Lifton Laboratory, Yale University School of Medicine

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.44	.;T;.;T;.;.;.
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D;D;D;.;D;.;D
M_CAP	Benign	0.064	D
MetaRNN	Pathogenic	0.80	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.080	D
MutationAssessor	Uncertain	2.4	M;M;M;M;M;M;M
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-2.5	N;N;D;N;N;N;N
REVEL	Uncertain	0.40
Sift	Uncertain	0.0020	D;D;D;D;D;D;D
Sift4G	Uncertain	0.0090	D;D;D;D;D;D;D
Polyphen		1.0	D;D;D;D;.;D;.
Vest4		0.79
MutPred		0.62		Loss of catalytic residue at A230 (P = 0.0085);Loss of catalytic residue at A230 (P = 0.0085);Loss of catalytic residue at A230 (P = 0.0085);Loss of catalytic residue at A230 (P = 0.0085);Loss of catalytic residue at A230 (P = 0.0085);Loss of catalytic residue at A230 (P = 0.0085);Loss of catalytic residue at A230 (P = 0.0085);
MVP		0.84
MPC		1.7
ClinPred		0.97	D
GERP RS		6.0
Varity_R		0.37
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs386352339; hg19: chr1-107867346; COSMIC: COSV53976121;