chr19-5828039-C-G

Position:

• chr19-5828039-C-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_004558.5(NRTN):​c.460C>G​(p.Leu154Val) 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 Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L154R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NRTN NM_004558.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.65

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14586121).
• BP6: Variant 19-5828039-C-G is Benign according to our data. Variant chr19-5828039-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 2524818.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NRTN	NM_004558.5	c.460C>G	p.Leu154Val	missense_variant	3/3	ENST00000303212.3
NRTN	XM_047438890.1	c.460C>G	p.Leu154Val	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NRTN	ENST00000303212.3	c.460C>G	p.Leu154Val	missense_variant	3/3	1	NM_004558.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 07, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.080	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	16
DANN	Benign	0.88
DEOGEN2	Uncertain	0.49	T
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.46	T
M_CAP	Pathogenic	0.65	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	-0.055	N
MutationTaster	Benign	1.0	N
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-0.55	N
REVEL	Benign	0.27
Sift	Benign	0.70	T
Sift4G	Benign	0.94	T
Polyphen		0.0	B
Vest4		0.12
MutPred		0.53		Loss of stability (P = 0.0755);
MVP		0.72
MPC		0.61
ClinPred		0.064	T
GERP RS		1.7
Varity_R		0.14
gMVP		0.42

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-5828050;