17-9022493-C-T

Variant names:

• chr17-9022493-C-T
• rs376332478
• NM_004822.3:c.120C>T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_004822.3(NTN1):​c.120C>T​(p.Pro40Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00261 in 1,541,148 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0018 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0027 (6 hom.)
• Consequence: NTN1 NM_004822.3 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -0.520
• Publications: 0 publications found

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

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 17-9022493-C-T is Benign according to our data. Variant chr17-9022493-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3049358.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.52 with no splicing effect.
• BS2: High AC in GnomAd4 at 271 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NTN1	NM_004822.3	c.120C>T	p.Pro40Pro	synonymous_variant	Exon 2 of 7	ENST00000173229.7	NP_004813.2
NTN1	XM_006721595.4	c.120C>T	p.Pro40Pro	synonymous_variant	Exon 2 of 7		XP_006721658.1
NTN1	XM_047437096.1	c.120C>T	p.Pro40Pro	synonymous_variant	Exon 2 of 7		XP_047293052.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NTN1	ENST00000173229.7	c.120C>T	p.Pro40Pro	synonymous_variant	Exon 2 of 7	1	NM_004822.3	ENSP00000173229.2

Frequencies

GnomAD3 genomes AF: 0.00177 AC: 270 AN: 152120 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00209

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000413

Gnomad FIN AF: 0.000945

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00294

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.00168 AC: 230 AN: 136552 AF XY: 0.00172

Gnomad AFR exome AF: 0.000755

Gnomad AMR exome AF: 0.00187

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000900

Gnomad NFE exome AF: 0.00257

Gnomad OTH exome AF: 0.00220

GnomAD4 exome AF: 0.00270 AC: 3747 AN: 1388916 Hom.: 6 Cov.: 31 AF XY: 0.00266 AC XY: 1825 AN XY: 685762

African (AFR) AF: 0.000316 AC: 10 AN: 31670

American (AMR) AF: 0.00184 AC: 67 AN: 36336

Ashkenazi Jewish (ASJ) AF: 0.0000399 AC: 1 AN: 25034

East Asian (EAS) AF: 0.00 AC: 0 AN: 35892

South Asian (SAS) AF: 0.00135 AC: 107 AN: 79212

European-Finnish (FIN) AF: 0.00138 AC: 52 AN: 37754

Middle Eastern (MID) AF: 0.000352 AC: 2 AN: 5676

European-Non Finnish (NFE) AF: 0.00314 AC: 3389 AN: 1079524

Other (OTH) AF: 0.00206 AC: 119 AN: 57818

GnomAD4 genome AF: 0.00178 AC: 271 AN: 152232 Hom.: 0 Cov.: 33 AF XY: 0.00165 AC XY: 123 AN XY: 74436

African (AFR) AF: 0.000577 AC: 24 AN: 41580

American (AMR) AF: 0.00209 AC: 32 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5148

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4832

European-Finnish (FIN) AF: 0.000945 AC: 10 AN: 10584

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00294 AC: 200 AN: 67998

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.00171 Hom.: 0

Bravo AF: 0.00186

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

NTN1-related disorder Benign:1

Jul 22, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Jul 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NTN1: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	12
DANN	Benign	0.96
PhyloP100		-0.52
Mutation Taster		=99/1	polymorphism

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: rs376332478; hg19: chr17-8925810;