Genetic Variant NM_004822.3:c.274C>T (chr17-9022647-C-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_004822.3(NTN1):c.274C>T(p.His92Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000000709 in 1,410,868 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. H92N) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

NTN1
NM_004822.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.57

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: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.39930183).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NTN1	NM_004822.3 link	c.274C>T	p.His92Tyr	missense_variant	Exon 2 of 7	ENST00000173229.7	NP_004813.2	O95631
NTN1	XM_006721595.4 link	c.274C>T	p.His92Tyr	missense_variant	Exon 2 of 7		XP_006721658.1	O95631
NTN1	XM_047437096.1 link	c.274C>T	p.His92Tyr	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.274C>T	p.His92Tyr	missense_variant	Exon 2 of 7	1	NM_004822.3	ENSP00000173229.2		O95631

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.09e-7

AC:

AN:

1410868

Hom.:

Cov.:

AF XY:

0.00000143

AC XY:

AN XY:

697604

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31854

American (AMR)

AF:

0.00

AC:

AN:

37342

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25322

East Asian (EAS)

AF:

0.00

AC:

AN:

36108

South Asian (SAS)

AF:

0.00

AC:

AN:

80672

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47978

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5724

European-Non Finnish (NFE)

AF:

9.20e-7

AC:

AN:

1087342

Other (OTH)

AF:

0.00

AC:

AN:

58526

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

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Uncertain

0.050

BayesDel_noAF

Benign

-0.17

CADD

Uncertain

(source)

DANN

Uncertain

0.97

DEOGEN2

Uncertain

0.55

Eigen

Benign

-0.11

Eigen_PC

Benign

0.050

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.84

M_CAP

Benign

0.043

MetaRNN

Benign

0.40

MetaSVM

Benign

-0.55

MutationAssessor

Uncertain

2.2

PhyloP100

4.6

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

-1.3

REVEL

Uncertain

0.36

Sift

Benign

0.34

Sift4G

Benign

0.34

Polyphen

0.0060

Vest4

0.55

MutPred

0.59

Loss of disorder (P = 0.0406);

MVP

0.64

ClinPred

0.86

GERP RS

4.8

Varity_R

0.51

gMVP

0.70

Mutation Taster

=67/33

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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NM_004822.3:c.274C>T

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