Genetic Variant NTN5:p.Glu469Gln (chr19-48661742-C-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_145807.4(NTN5):c.1405G>C(p.Glu469Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000726 in 1,376,724 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E469K) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.3e-7 ( 0 hom. )

Consequence

NTN5
NM_145807.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.240

Publications

0 publications found

Variant links:

Genes affected

NTN5 (HGNC:25208): (netrin 5) Predicted to enable signaling receptor binding activity. Predicted to be involved in animal organ morphogenesis; neuron projection development; and tissue development. Predicted to be located in extracellular region. Predicted to be active in basement membrane. [provided by Alliance of Genome Resources, Apr 2022]

NTN5 links:

SEC1P (HGNC:):

SEC1P links:

SEC1P (HGNC:44149): (secretory blood group 1, pseudogene) Predicted to enable galactoside 2-alpha-L-fucosyltransferase activity. Predicted to act upstream of or within protein glycosylation. [provided by Alliance of Genome Resources, Apr 2022]

SEC1P links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.062002093).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NTN5	NM_145807.4 link	c.1405G>C	p.Glu469Gln	missense_variant	Exon 7 of 7	ENST00000270235.11	NP_665806.1	Q8WTR8-1
SEC1P	NR_004401.2 link	n.109-1455C>G		intron_variant	Intron 1 of 4
NTN5	XM_011526443.4 link	c.*1435G>C		downstream_gene_variant			XP_011524745.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NTN5	ENST00000270235.11 link	c.1405G>C	p.Glu469Gln	missense_variant	Exon 7 of 7	1	NM_145807.4	ENSP00000270235.4		Q8WTR8-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.26e-7

AC:

AN:

1376724

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

684306

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

28296

American (AMR)

AF:

0.00

AC:

AN:

34998

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23468

East Asian (EAS)

AF:

0.00

AC:

AN:

32620

South Asian (SAS)

AF:

0.0000127

AC:

AN:

78996

European-Finnish (FIN)

AF:

0.00

AC:

AN:

35722

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5130

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1080814

Other (OTH)

AF:

0.00

AC:

AN:

56680

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.60

CADD

Benign

9.0

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.0024

Eigen

Benign

-0.77

Eigen_PC

Benign

-0.66

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.50

M_CAP

Benign

0.0061

MetaRNN

Benign

0.062

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.0

PhyloP100

0.24

PrimateAI

Uncertain

0.74

PROVEAN

Benign

0.070

REVEL

Benign

0.0080

Sift

Benign

0.38

Sift4G

Benign

0.25

Polyphen

0.030

Vest4

0.097

MutPred

0.33

Gain of ubiquitination at K464 (P = 0.1317);

MVP

0.15

MPC

0.32

ClinPred

0.17

GERP RS

0.27

Varity_R

0.066

gMVP

0.42

Mutation Taster

=93/7

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over