12-95787450-C-A

Position:

• chr12-95787450-C-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_021229.4(NTN4):​c.74G>T​(p.Gly25Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00438 in 1,613,942 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0037 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0044 (24 hom.)
• Consequence: NTN4 NM_021229.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.03

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]

NTN4 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004955709).
• BP6: Variant 12-95787450-C-A is Benign according to our data. Variant chr12-95787450-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 776902.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NTN4	NM_021229.4	c.74G>T	p.Gly25Val	missense_variant	2/10	ENST00000343702.9	NP_067052.2
NTN4	NM_001329700.2	c.74G>T	p.Gly25Val	missense_variant	2/9		NP_001316629.1
NTN4	NM_001329701.2	c.-38G>T		5_prime_UTR_variant	2/10		NP_001316630.1
NTN4	NM_001329702.2	c.-38G>T		5_prime_UTR_variant	2/10		NP_001316631.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NTN4	ENST00000343702.9	c.74G>T	p.Gly25Val	missense_variant	2/10	1	NM_021229.4	ENSP00000340998.4

Frequencies

GnomAD3 genomes AF: 0.00366 AC: 557 AN: 152216 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000989

Gnomad AMI AF: 0.0186

Gnomad AMR AF: 0.00321

Gnomad ASJ AF: 0.0161

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00496

Gnomad FIN AF: 0.00188

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00497

Gnomad OTH AF: 0.00526

GnomAD3 exomes AF: 0.00449 AC: 1126 AN: 251018 Hom.: 7 AF XY: 0.00476 AC XY: 646 AN XY: 135736

Gnomad AFR exome AF: 0.000740

Gnomad AMR exome AF: 0.00298

Gnomad ASJ exome AF: 0.0163

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00415

Gnomad FIN exome AF: 0.00231

Gnomad NFE exome AF: 0.00554

Gnomad OTH exome AF: 0.00669

GnomAD4 exome AF: 0.00445 AC: 6503 AN: 1461608 Hom.: 24 Cov.: 32 AF XY: 0.00450 AC XY: 3272 AN XY: 727102

Gnomad4 AFR exome AF: 0.00102

Gnomad4 AMR exome AF: 0.00356

Gnomad4 ASJ exome AF: 0.0158

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00470

Gnomad4 FIN exome AF: 0.00242

Gnomad4 NFE exome AF: 0.00449

Gnomad4 OTH exome AF: 0.00502

GnomAD4 genome AF: 0.00366 AC: 558 AN: 152334 Hom.: 3 Cov.: 32 AF XY: 0.00367 AC XY: 273 AN XY: 74482

Gnomad4 AFR AF: 0.000986

Gnomad4 AMR AF: 0.00320

Gnomad4 ASJ AF: 0.0161

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00518

Gnomad4 FIN AF: 0.00188

Gnomad4 NFE AF: 0.00497

Gnomad4 OTH AF: 0.00521

Alfa AF: 0.00522 Hom.: 5

Bravo AF: 0.00372

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00640 AC: 55

ExAC AF: 0.00444 AC: 539

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.00643

EpiControl AF: 0.00753

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	NTN4: BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 11, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.013	T;.
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.52	D
LIST_S2	Benign	0.77	T;T
M_CAP	Benign	0.0097	T
MetaRNN	Benign	0.0050	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.81	L;L
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.6	N;N
REVEL	Benign	0.13
Sift	Benign	0.084	T;T
Sift4G	Uncertain	0.029	D;D
Polyphen		0.45	P;P
Vest4		0.48
MVP		0.36
MPC		0.55
ClinPred		0.016	T
GERP RS		5.8
Varity_R		0.15
gMVP		0.57

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: rs34684875; hg19: chr12-96181228;