Genetic Variant NM_004822.3:c.235G>A (chr17-9022608-G-A) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_004822.3(NTN1):c.235G>A(p.Val79Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000226 in 1,550,660 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

NTN1
NM_004822.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.21

Publications

0 publications found

Variant links:

Genes affected

NTN1 (HGNC:8029): (netrin 1) Netrin is included in a family of laminin-related secreted proteins. The function of this gene has not yet been defined; however, netrin is thought to be involved in axon guidance and cell migration during development. Mutations and loss of expression of netrin suggest that variation in netrin may be involved in cancer development. [provided by RefSeq, Jul 2008]

NTN1 Gene-Disease associations (from GenCC):

mirror movements 4
Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
familial congenital mirror movements
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
multiple congenital anomalies/dysmorphic syndrome
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

NTN1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.14213556).

BS2

High AC in GnomAd4 at 17 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NTN1	NM_004822.3 link	c.235G>A	p.Val79Met	missense_variant	Exon 2 of 7	ENST00000173229.7	NP_004813.2	O95631
NTN1	XM_006721595.4 link	c.235G>A	p.Val79Met	missense_variant	Exon 2 of 7		XP_006721658.1	O95631
NTN1	XM_047437096.1 link	c.235G>A	p.Val79Met	missense_variant	Exon 2 of 7		XP_047293052.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NTN1	ENST00000173229.7 link	c.235G>A	p.Val79Met	missense_variant	Exon 2 of 7	1	NM_004822.3	ENSP00000173229.2		O95631

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000410

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000137

AC:

AN:

145612

AF XY:

0.0000126

show subpopulations

Gnomad AFR exome

AF:

0.000301

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000129

AC:

AN:

1398516

Hom.:

Cov.:

AF XY:

0.0000145

AC XY:

AN XY:

690236

show subpopulations

African (AFR)

AF:

0.000410

AC:

AN:

31684

American (AMR)

AF:

0.0000276

AC:

AN:

36224

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25152

East Asian (EAS)

AF:

0.00

AC:

AN:

35816

South Asian (SAS)

AF:

0.0000126

AC:

AN:

79680

European-Finnish (FIN)

AF:

0.00

AC:

AN:

45730

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5694

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1080506

Other (OTH)

AF:

0.0000517

AC:

AN:

58030

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.528

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000112

AC:

AN:

152144

Hom.:

Cov.:

AF XY:

0.0000942

AC XY:

AN XY:

74332

show subpopulations

African (AFR)

AF:

0.000410

AC:

AN:

41456

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5160

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68006

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.000113

ExAC

AF:

0.0000454

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 25, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.235G>A (p.V79M) alteration is located in exon 2 (coding exon 1) of the NTN1 gene. This alteration results from a G to A substitution at nucleotide position 235, causing the valine (V) at amino acid position 79 to be replaced by a methionine (M). 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

0.11

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.18

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.49

Eigen

Uncertain

0.37

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.95

M_CAP

Uncertain

0.24

MetaRNN

Benign

0.14

MetaSVM

Benign

-0.29

MutationAssessor

Benign

1.5

PhyloP100

5.2

PrimateAI

Pathogenic

0.89

PROVEAN

Benign

-0.26

REVEL

Uncertain

0.32

Sift

Benign

0.11

Sift4G

Benign

0.092

Polyphen

0.84

Vest4

0.39

MutPred

0.57

Loss of sheet (P = 0.0457);

MVP

0.65

ClinPred

0.23

GERP RS

4.6

Varity_R

0.31

gMVP

0.59

Mutation Taster

=50/50

(source)

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

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NM_004822.3:c.235G>A

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