Genetic Variant NM_145807.4:c.1405G>A (chr19-48661742-C-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_145807.4(NTN5):c.1405G>A(p.Glu469Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000556 in 1,528,814 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. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000058 ( 0 hom. )

Consequence

NTN5
NM_145807.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.030737936).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NTN5	NM_145807.4 link	c.1405G>A	p.Glu469Lys	missense_variant	Exon 7 of 7	ENST00000270235.11	NP_665806.1	Q8WTR8-1
SEC1P	NR_004401.2 link	n.109-1455C>T		intron_variant	Intron 1 of 4
NTN5	XM_011526443.4 link	c.*1435G>A		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>A	p.Glu469Lys	missense_variant	Exon 7 of 7	1	NM_145807.4	ENSP00000270235.4		Q8WTR8-1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152092

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000545

AC:

AN:

146786

AF XY:

0.0000588

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000114

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000445

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000581

AC:

AN:

1376722

Hom.:

Cov.:

AF XY:

0.0000701

AC XY:

AN XY:

684304

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:

0.0000920

AC:

AN:

32620

South Asian (SAS)

AF:

0.000241

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:

0.0000500

AC:

AN:

1080812

Other (OTH)

AF:

0.0000706

AC:

AN:

56680

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

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

AF:

0.0000329

AC:

AN:

152092

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74312

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41424

American (AMR)

AF:

0.00

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10574

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68000

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.0000714

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 29, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1405G>A (p.E469K) alteration is located in exon 7 (coding exon 6) of the NTN5 gene. This alteration results from a G to A substitution at nucleotide position 1405, causing the glutamic acid (E) at amino acid position 469 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.56

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.0024

Eigen

Benign

-0.87

Eigen_PC

Benign

-0.73

FATHMM_MKL

Benign

0.40

LIST_S2

Benign

0.58

M_CAP

Benign

0.0083

MetaRNN

Benign

0.031

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.49

PhyloP100

0.24

PrimateAI

Uncertain

0.78

PROVEAN

Benign

0.45

REVEL

Benign

0.012

Sift

Benign

0.72

Sift4G

Benign

0.21

Polyphen

0.0060

Vest4

0.073

MVP

0.10

MPC

0.36

ClinPred

0.055

GERP RS

0.27

Varity_R

0.047

gMVP

0.50

Mutation Taster

=97/3

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over