Genetic Variant NM_004558.5:c.474G>C (chr19-5828053-G-C) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_004558.5(NRTN):c.474G>C(p.Arg158Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0517 in 1,427,226 control chromosomes in the GnomAD database, including 2,535 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.071 ( 520 hom., cov: 32)

Exomes 𝑓: 0.049 ( 2015 hom. )

Consequence

NRTN
NM_004558.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.601

Publications

6 publications found

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 was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.39).

BP6

Variant 19-5828053-G-C is Benign according to our data. Variant chr19-5828053-G-C is described in ClinVar as Benign. ClinVar VariationId is 259428.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.601 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.128 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NRTN	NM_004558.5 link	c.474G>C	p.Arg158Arg	synonymous_variant	Exon 3 of 3	ENST00000303212.3	NP_004549.1	Q99748
NRTN	XM_047438890.1 link	c.474G>C	p.Arg158Arg	synonymous_variant	Exon 2 of 2		XP_047294846.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NRTN	ENST00000303212.3 link	c.474G>C	p.Arg158Arg	synonymous_variant	Exon 3 of 3	1	NM_004558.5	ENSP00000302648.1		Q99748

Frequencies

GnomAD3 genomes

AF:

0.0707

AC:

10658

AN:

150716

Hom.:

520

Cov.:

show subpopulations

Gnomad AFR

AF:

0.130

Gnomad AMI

AF:

0.0208

Gnomad AMR

AF:

0.0480

Gnomad ASJ

AF:

0.0665

Gnomad EAS

AF:

0.103

Gnomad SAS

AF:

0.130

Gnomad FIN

AF:

0.0291

Gnomad MID

AF:

0.0350

Gnomad NFE

AF:

0.0397

Gnomad OTH

AF:

0.0741

GnomAD2 exomes

AF:

0.0503

AC:

2492

AN:

49592

AF XY:

0.0570

show subpopulations

Gnomad AFR exome

AF:

0.103

Gnomad AMR exome

AF:

0.0257

Gnomad ASJ exome

AF:

0.0530

Gnomad EAS exome

AF:

0.0723

Gnomad FIN exome

AF:

0.0200

Gnomad NFE exome

AF:

0.0347

Gnomad OTH exome

AF:

0.0478

GnomAD4 exome

AF:

0.0494

AC:

63114

AN:

1276404

Hom.:

2015

Cov.:

AF XY:

0.0513

AC XY:

32187

AN XY:

627342

show subpopulations

African (AFR)

AF:

0.129

AC:

3294

AN:

25460

American (AMR)

AF:

0.0340

AC:

636

AN:

18700

Ashkenazi Jewish (ASJ)

AF:

0.0652

AC:

1348

AN:

20668

East Asian (EAS)

AF:

0.0728

AC:

2055

AN:

28226

South Asian (SAS)

AF:

0.128

AC:

8145

AN:

63444

European-Finnish (FIN)

AF:

0.0290

AC:

937

AN:

32294

Middle Eastern (MID)

AF:

0.0547

AC:

216

AN:

3952

European-Non Finnish (NFE)

AF:

0.0420

AC:

43280

AN:

1030842

Other (OTH)

AF:

0.0606

AC:

3203

AN:

52818

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

3204

6408

9613

12817

16021

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1860

3720

5580

7440

9300

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0708

AC:

10685

AN:

150822

Hom.:

520

Cov.:

AF XY:

0.0715

AC XY:

5260

AN XY:

73596

show subpopulations

African (AFR)

AF:

0.131

AC:

5413

AN:

41440

American (AMR)

AF:

0.0480

AC:

730

AN:

15224

Ashkenazi Jewish (ASJ)

AF:

0.0665

AC:

227

AN:

3412

East Asian (EAS)

AF:

0.103

AC:

530

AN:

5150

South Asian (SAS)

AF:

0.131

AC:

631

AN:

4824

European-Finnish (FIN)

AF:

0.0291

AC:

305

AN:

10486

Middle Eastern (MID)

AF:

0.0308

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0397

AC:

2659

AN:

66994

Other (OTH)

AF:

0.0776

AC:

162

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

503

1006

1508

2011

2514

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

240

360

480

600

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0536

Hom.:

Bravo

AF:

0.0722

Asia WGS

AF:

0.154

AC:

523

AN:

3394

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.39

CADD

Benign

(source)

DANN

Benign

0.89

PhyloP100

0.60

Mutation Taster

=84/16

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over