NM_004822.3:c.342G>A

Variant names:

• chr17-9022715-G-A
• rs73262152
• NM_004822.3:c.342G>A

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP7

The NM_004822.3(NTN1):​c.342G>A​(p.Pro114Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000069 in 1,450,296 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. Synonymous variant affecting the same amino acid position (i.e. P114P) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: NTN1 NM_004822.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.31
• 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: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP7: Synonymous conserved (PhyloP=1.31 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NTN1	NM_004822.3	c.342G>A	p.Pro114Pro	synonymous_variant	Exon 2 of 7	ENST00000173229.7	NP_004813.2
NTN1	XM_006721595.4	c.342G>A	p.Pro114Pro	synonymous_variant	Exon 2 of 7		XP_006721658.1
NTN1	XM_047437096.1	c.342G>A	p.Pro114Pro	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.342G>A	p.Pro114Pro	synonymous_variant	Exon 2 of 7	1	NM_004822.3	ENSP00000173229.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.90e-7 AC: 1 AN: 1450296 Hom.: 0 Cov.: 32 AF XY: 0.00000139 AC XY: 1 AN XY: 720682

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32994

American (AMR) AF: 0.00 AC: 0 AN: 43610

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25946

East Asian (EAS) AF: 0.0000259 AC: 1 AN: 38652

South Asian (SAS) AF: 0.00 AC: 0 AN: 84524

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1107416

Other (OTH) AF: 0.00 AC: 0 AN: 59992

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	12
DANN	Benign	0.97
PhyloP100		1.3

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: rs73262152; hg19: chr17-8926032;