rs17288108

Positions:

• chr12-95738117-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_021229.4(NTN4):​c.613T>C​(p.Tyr205His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.155 in 1,613,474 control chromosomes in the GnomAD database, including 21,298 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in Lovd as Benign (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.12 (1509 hom., cov: 32)
  • Exomes 𝑓: 0.16 (19789 hom.)
• Consequence: NTN4 NM_021229.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0250

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0013000667).
• BP6: Variant 12-95738117-A-G is Benign according to our data. Variant chr12-95738117-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.173 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NTN4	NM_021229.4	c.613T>C	p.Tyr205His	missense_variant	3/10	ENST00000343702.9	NP_067052.2
NTN4	NM_001329700.2	c.613T>C	p.Tyr205His	missense_variant	3/9		NP_001316629.1
NTN4	NM_001329701.2	c.502T>C	p.Tyr168His	missense_variant	3/10		NP_001316630.1
NTN4	NM_001329702.2	c.502T>C	p.Tyr168His	missense_variant	3/10		NP_001316631.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NTN4	ENST00000343702.9	c.613T>C	p.Tyr205His	missense_variant	3/10	1	NM_021229.4	ENSP00000340998.4

Frequencies

GnomAD3 genomes AF: 0.121 AC: 18338 AN: 152116 Hom.: 1510 Cov.: 32

Gnomad AFR AF: 0.0299

Gnomad AMI AF: 0.412

Gnomad AMR AF: 0.103

Gnomad ASJ AF: 0.175

Gnomad EAS AF: 0.0252

Gnomad SAS AF: 0.0968

Gnomad FIN AF: 0.162

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.176

Gnomad OTH AF: 0.123

GnomAD3 exomes AF: 0.127 AC: 31781 AN: 250710 Hom.: 2488 AF XY: 0.131 AC XY: 17804 AN XY: 135466

Gnomad AFR exome AF: 0.0259

Gnomad AMR exome AF: 0.0706

Gnomad ASJ exome AF: 0.172

Gnomad EAS exome AF: 0.0249

Gnomad SAS exome AF: 0.105

Gnomad FIN exome AF: 0.163

Gnomad NFE exome AF: 0.169

Gnomad OTH exome AF: 0.140

GnomAD4 exome AF: 0.158 AC: 231578 AN: 1461244 Hom.: 19789 Cov.: 32 AF XY: 0.158 AC XY: 114705 AN XY: 726914

Gnomad4 AFR exome AF: 0.0250

Gnomad4 AMR exome AF: 0.0726

Gnomad4 ASJ exome AF: 0.170

Gnomad4 EAS exome AF: 0.0112

Gnomad4 SAS exome AF: 0.108

Gnomad4 FIN exome AF: 0.167

Gnomad4 NFE exome AF: 0.175

Gnomad4 OTH exome AF: 0.151

GnomAD4 genome AF: 0.120 AC: 18335 AN: 152230 Hom.: 1509 Cov.: 32 AF XY: 0.118 AC XY: 8798 AN XY: 74418

Gnomad4 AFR AF: 0.0298

Gnomad4 AMR AF: 0.103

Gnomad4 ASJ AF: 0.175

Gnomad4 EAS AF: 0.0247

Gnomad4 SAS AF: 0.0969

Gnomad4 FIN AF: 0.162

Gnomad4 NFE AF: 0.176

Gnomad4 OTH AF: 0.123

Alfa AF: 0.159 Hom.: 5209

Bravo AF: 0.111

TwinsUK AF: 0.175 AC: 648

ALSPAC AF: 0.170 AC: 657

ESP6500AA AF: 0.0311 AC: 137

ESP6500EA AF: 0.175 AC: 1507

ExAC AF: 0.126 AC: 15246

Asia WGS AF: 0.0590 AC: 206 AN: 3478

EpiCase AF: 0.168

EpiControl AF: 0.169

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	16
DANN	Benign	0.84
DEOGEN2	Benign	0.15	T;.;.;.;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.77	T;.;T;T;T
MetaRNN	Benign	0.0013	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.48	N;.;.;N;.
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.75	N;N;N;N;N
REVEL	Benign	0.086
Sift	Benign	0.55	T;T;T;T;T
Sift4G	Benign	0.54	T;T;T;T;.
Polyphen		0.0	B;.;.;B;.
Vest4		0.17
MPC		0.44
ClinPred		0.0011	T
GERP RS		1.6
Varity_R		0.046
gMVP		0.70

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: rs17288108; hg19: chr12-96131895; COSMIC: COSV59220757;