NM_021229.4:c.613T>C

Variant names:

• chr12-95738117-A-G
• rs17288108
• NM_021229.4:c.613T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong 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. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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
• Publications: 28 publications found

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]

PGAM1P5 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0013000667).
• 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 rank	MANE	Protein	UniProt
NTN4	NM_021229.4	c.613T>C	p.Tyr205His	missense_variant	Exon 3 of 10	ENST00000343702.9	NP_067052.2
NTN4	NM_001329700.2	c.613T>C	p.Tyr205His	missense_variant	Exon 3 of 9		NP_001316629.1
NTN4	NM_001329701.2	c.502T>C	p.Tyr168His	missense_variant	Exon 3 of 10		NP_001316630.1
NTN4	NM_001329702.2	c.502T>C	p.Tyr168His	missense_variant	Exon 3 of 10		NP_001316631.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NTN4	ENST00000343702.9	c.613T>C	p.Tyr205His	missense_variant	Exon 3 of 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

GnomAD2 exomes AF: 0.127 AC: 31781 AN: 250710 AF XY: 0.131

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 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

African (AFR) AF: 0.0250 AC: 836 AN: 33460

American (AMR) AF: 0.0726 AC: 3245 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.170 AC: 4441 AN: 26130

East Asian (EAS) AF: 0.0112 AC: 443 AN: 39688

South Asian (SAS) AF: 0.108 AC: 9328 AN: 86218

European-Finnish (FIN) AF: 0.167 AC: 8914 AN: 53414

Middle Eastern (MID) AF: 0.114 AC: 660 AN: 5766

European-Non Finnish (NFE) AF: 0.175 AC: 194595 AN: 1111490

Other (OTH) AF: 0.151 AC: 9116 AN: 60374

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

African (AFR) AF: 0.0298 AC: 1240 AN: 41560

American (AMR) AF: 0.103 AC: 1569 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.175 AC: 607 AN: 3468

East Asian (EAS) AF: 0.0247 AC: 128 AN: 5186

South Asian (SAS) AF: 0.0969 AC: 467 AN: 4818

European-Finnish (FIN) AF: 0.162 AC: 1714 AN: 10590

Middle Eastern (MID) AF: 0.129 AC: 38 AN: 294

European-Non Finnish (NFE) AF: 0.176 AC: 11937 AN: 68006

Other (OTH) AF: 0.123 AC: 259 AN: 2110

Alfa AF: 0.151 Hom.: 6772

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;.
PhyloP100		0.025
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
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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