rs79744308

chr19-5827754-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_004558.5(NRTN):c.175G>A(p.Ala59Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0457 in 1,218,970 control chromosomes in the GnomAD database, including 1,520 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.053 (264 hom., cov: 31)
  • Exomes 𝑓: 0.045 (1256 hom.)
• Consequence: NRTN NM_004558.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.97

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0011277497).
• BP6: Variant 19-5827754-G-A is Benign according to our data. Variant chr19-5827754-G-A is described in ClinVar as [Benign]. Clinvar id is 259427.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.122 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NRTN	NM_004558.5	c.175G>A	p.Ala59Thr	missense_variant	3/3	ENST00000303212.3
NRTN	XM_047438890.1	c.175G>A	p.Ala59Thr	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NRTN	ENST00000303212.3	c.175G>A	p.Ala59Thr	missense_variant	3/3	1	NM_004558.5	P1

Frequencies

GnomAD3 genomes AF: 0.0534 AC: 8068 AN: 151134 Hom.: 266 Cov.: 31

Gnomad AFR AF: 0.0707

Gnomad AMI AF: 0.0209

Gnomad AMR AF: 0.0428

Gnomad ASJ AF: 0.0670

Gnomad EAS AF: 0.103

Gnomad SAS AF: 0.130

Gnomad FIN AF: 0.0281

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0396

Gnomad OTH AF: 0.0612

GnomAD3 exomes AF: 0.0451 AC: 2566 AN: 56878 Hom.: 77 AF XY: 0.0467 AC XY: 1513 AN XY: 32426

Gnomad AFR exome AF: 0.0664

Gnomad AMR exome AF: 0.0234

Gnomad ASJ exome AF: 0.0421

Gnomad EAS exome AF: 0.0864

Gnomad SAS exome AF: 0.124

Gnomad FIN exome AF: 0.0278

Gnomad NFE exome AF: 0.0363

Gnomad OTH exome AF: 0.0421

GnomAD4 exome AF: 0.0446 AC: 47657 AN: 1067722 Hom.: 1256 Cov.: 30 AF XY: 0.0448 AC XY: 22832 AN XY: 509236

Gnomad4 AFR exome AF: 0.0689

Gnomad4 AMR exome AF: 0.0270

Gnomad4 ASJ exome AF: 0.0618

Gnomad4 EAS exome AF: 0.0667

Gnomad4 SAS exome AF: 0.138

Gnomad4 FIN exome AF: 0.0237

Gnomad4 NFE exome AF: 0.0412

Gnomad4 OTH exome AF: 0.0550

GnomAD4 genome AF: 0.0534 AC: 8079 AN: 151248 Hom.: 264 Cov.: 31 AF XY: 0.0544 AC XY: 4020 AN XY: 73954

Gnomad4 AFR AF: 0.0707

Gnomad4 AMR AF: 0.0428

Gnomad4 ASJ AF: 0.0670

Gnomad4 EAS AF: 0.103

Gnomad4 SAS AF: 0.130

Gnomad4 FIN AF: 0.0281

Gnomad4 NFE AF: 0.0396

Gnomad4 OTH AF: 0.0649

Alfa AF: 0.0434 Hom.: 25

Bravo AF: 0.0525

TwinsUK AF: 0.0469 AC: 174

ALSPAC AF: 0.0449 AC: 173

ESP6500AA AF: 0.0431 AC: 113

ESP6500EA AF: 0.0350 AC: 180

ExAC AF: 0.0423 AC: 4442

Asia WGS AF: 0.164 AC: 569 AN: 3472

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.44
Cadd	Benign	21
Dann	Uncertain	1.0
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.56	T
MetaRNN	Benign	0.0011	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	2.0	M
MutationTaster	Benign	1.0	N
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-0.10	N
REVEL	Benign	0.19
Sift	Uncertain	0.022	D
Sift4G	Benign	0.17	T
Polyphen		0.44	B
Vest4		0.022
MPC		1.5
ClinPred		0.011	T
GERP RS		4.1
Varity_R		0.099
gMVP		0.33

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

Other links and lift over

dbSNP: rs79744308; hg19: chr19-5827765; COSMIC: COSV54605610; COSMIC: COSV54605610;