12-95683710-C-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_021229.4(NTN4):c.1182G>A(p.Pro394=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00119 in 1,599,610 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0025 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (2 hom.)
• Consequence: NTN4 NM_021229.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.00009276
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -3.46

Genes affected

NTN4 (HGNC:13658): (netrin 4) This gene encodes a member of the netrin family of proteins, which function in various biological processes including axon guidance, tumorogenesis, and angiogenesis. Netrins are laminin-related proteins that have an N-terminal laminin-type domain, epidermal growth factor-like repeat domain, and a positively charged heparin-binding domain at the C-terminus. The protein encoded by this gene is involved in processes including neurite growth and migration, angiogenesis and mural cell adhesion to endothelial cells. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2016]

ACMG classification

Verdict is Benign. Variant got -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 12-95683710-C-T is Benign according to our data. Variant chr12-95683710-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2643221.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-3.46 with no splicing effect.
• BS2: High Homozygotes in GnomAd at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NTN4	NM_021229.4	c.1182G>A	p.Pro394=	splice_region_variant, synonymous_variant	6/10	ENST00000343702.9
NTN4	NM_001329700.2	c.1182G>A	p.Pro394=	splice_region_variant, synonymous_variant	6/9
NTN4	NM_001329701.2	c.1071G>A	p.Pro357=	splice_region_variant, synonymous_variant	6/10
NTN4	NM_001329702.2	c.1071G>A	p.Pro357=	splice_region_variant, synonymous_variant	6/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NTN4	ENST00000343702.9	c.1182G>A	p.Pro394=	splice_region_variant, synonymous_variant	6/10	1	NM_021229.4	P1

Frequencies

GnomAD3 genomes AF: 0.00252 AC: 384 AN: 152130 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00478

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00387

Gnomad ASJ AF: 0.0130

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000985

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.00174 AC: 388 AN: 222774 Hom.: 0 AF XY: 0.00142 AC XY: 170 AN XY: 119838

Gnomad AFR exome AF: 0.00543

Gnomad AMR exome AF: 0.00238

Gnomad ASJ exome AF: 0.0129

Gnomad EAS exome AF: 0.000121

Gnomad SAS exome AF: 0.000143

Gnomad FIN exome AF: 0.0000506

Gnomad NFE exome AF: 0.000867

Gnomad OTH exome AF: 0.00412

GnomAD4 exome AF: 0.00105 AC: 1526 AN: 1447362 Hom.: 2 Cov.: 31 AF XY: 0.000971 AC XY: 698 AN XY: 718662

Gnomad4 AFR exome AF: 0.00607

Gnomad4 AMR exome AF: 0.00263

Gnomad4 ASJ exome AF: 0.0140

Gnomad4 EAS exome AF: 0.0000513

Gnomad4 SAS exome AF: 0.000202

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000554

Gnomad4 OTH exome AF: 0.00297

GnomAD4 genome AF: 0.00253 AC: 385 AN: 152248 Hom.: 2 Cov.: 32 AF XY: 0.00235 AC XY: 175 AN XY: 74460

Gnomad4 AFR AF: 0.00479

Gnomad4 AMR AF: 0.00386

Gnomad4 ASJ AF: 0.0130

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000985

Gnomad4 OTH AF: 0.00427

Alfa AF: 0.00183 Hom.: 2

Bravo AF: 0.00298

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jan 01, 2023

NTN4: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	1.0
Dann	Benign	0.74

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000093
dbscSNV1_RF	Benign	0.0040
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: rs148907075; hg19: chr12-96077486; COSMIC: COSV59221042;