Variant chr19-5827997-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_004558.5(NRTN):c.418G>C(p.Val140Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000023 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

NRTN
NM_004558.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.41

Variant links:

Genes affected

NRTN (HGNC:8007): (neurturin) This gene encodes a secreted ligand of the TGF-beta (transforming growth factor-beta) superfamily of proteins. The encoded preproprotein is proteolytically processed to generate the mature protein. This protein signals through the RET receptor tyrosine kinase and a GPI-linked coreceptor, and promotes survival of neuronal populations. A neurturin mutation has been described in a family with Hirschsprung Disease. [provided by RefSeq, Aug 2016]

NRTN links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.27776855).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NRTN	NM_004558.5 linkuse as main transcript	c.418G>C	p.Val140Leu	missense_variant	3/3	ENST00000303212.3
NRTN	XM_047438890.1 linkuse as main transcript	c.418G>C	p.Val140Leu	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NRTN	ENST00000303212.3 linkuse as main transcript	c.418G>C	p.Val140Leu	missense_variant	3/3	1	NM_004558.5	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000329

AC:

AN:

91072

Hom.:

AF XY:

0.0000569

AC XY:

AN XY:

52736

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000209

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000229

AC:

AN:

1310128

Hom.:

Cov.:

AF XY:

0.00000464

AC XY:

AN XY:

647210

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000118

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000195

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 17, 2021

The c.418G>C (p.V140L) alteration is located in exon 2 (coding exon 2) of the NRTN gene. This alteration results from a G to C substitution at nucleotide position 418, causing the valine (V) at amino acid position 140 to be replaced by a leucine (L). 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

0.15

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.26

CADD

Benign

DANN

Benign

0.91

DEOGEN2

Benign

0.33

Eigen

Benign

-0.62

Eigen_PC

Benign

-0.53

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.70

M_CAP

Pathogenic

0.86

MetaRNN

Benign

0.28

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.34

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.94

PROVEAN

Benign

-0.26

REVEL

Benign

0.083

Sift

Benign

0.56

Sift4G

Benign

0.12

Polyphen

0.016

Vest4

0.077

MutPred

0.36

Loss of MoRF binding (P = 0.1016);

MVP

0.77

MPC

0.59

ClinPred

0.057

GERP RS

0.41

Varity_R

0.14

gMVP

0.56

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over