rs79744308

Variant names:

• chr19-5827754-G-A
• rs79744308
• NM_004558.5:c.175G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong 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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A59V) has been classified as Uncertain significance.

• 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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.97
• Publications: 12 publications found

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

Our verdict: Benign. The variant received -20 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 VariationId is 259427.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.122 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004558.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRTN	NM_004558.5	MANE Select	c.175G>A	p.Ala59Thr	missense	Exon 3 of 3	NP_004549.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRTN	ENST00000303212.3	TSL:1 MANE Select	c.175G>A	p.Ala59Thr	missense	Exon 3 of 3	ENSP00000302648.1
	NRTN	ENST00000879152.1		c.175G>A	p.Ala59Thr	missense	Exon 3 of 3	ENSP00000549211.1
	NRTN	ENST00000936080.1		c.175G>A	p.Ala59Thr	missense	Exon 3 of 3	ENSP00000606139.1

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

GnomAD2 exomes AF: 0.0451 AC: 2566 AN: 56878 AF XY: 0.0467

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 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

African (AFR) AF: 0.0689 AC: 1502 AN: 21806

American (AMR) AF: 0.0270 AC: 369 AN: 13664

Ashkenazi Jewish (ASJ) AF: 0.0618 AC: 758 AN: 12260

East Asian (EAS) AF: 0.0667 AC: 1605 AN: 24066

South Asian (SAS) AF: 0.138 AC: 3019 AN: 21944

European-Finnish (FIN) AF: 0.0237 AC: 466 AN: 19680

Middle Eastern (MID) AF: 0.0490 AC: 211 AN: 4304

European-Non Finnish (NFE) AF: 0.0412 AC: 37468 AN: 908954

Other (OTH) AF: 0.0550 AC: 2259 AN: 41044

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

African (AFR) AF: 0.0707 AC: 2913 AN: 41228

American (AMR) AF: 0.0428 AC: 652 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.0670 AC: 232 AN: 3462

East Asian (EAS) AF: 0.103 AC: 523 AN: 5092

South Asian (SAS) AF: 0.130 AC: 623 AN: 4788

European-Finnish (FIN) AF: 0.0281 AC: 292 AN: 10408

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0396 AC: 2681 AN: 67726

Other (OTH) AF: 0.0649 AC: 136 AN: 2096

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		2.0
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
Mutation Taster		=75/25	polymorphism (auto)

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