1-43936574-C-T

Variant names:

• chr1-43936574-C-T
• rs1459598751
• NM_057091.3:c.472C>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_057091.3(ARTN):​c.472C>T​(p.Arg158Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000658 in 152,058 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ARTN NM_057091.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.33
• Publications: 0 publications found

Genes affected

ARTN (HGNC:727): (artemin) This gene encodes a secreted ligand of the glial cell line-derived neurotrophic factor (GDNF) subfamily and TGF-beta (transforming growth factor-beta) superfamily of proteins. Ligands of this family bind various TGF-beta receptors leading to recruitment and activation of SMAD family transcription factors that regulate gene expression. The encoded preproprotein is proteolytically processed to generate each subunit of the disulfide-linked homodimer. This protein signals through the RET receptor and GFR alpha 3 coreceptor, and supports the survival of a number of peripheral neuron populations and at least one population of dopaminergic CNS neurons. This protein has also been shown to promote tumor growth, metastasis, and drug resistance in mammary carcinoma. [provided by RefSeq, Aug 2016]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.838

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_057091.3. 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
	ARTN	NM_057091.3	MANE Select	c.472C>T	p.Arg158Cys	missense	Exon 5 of 5	NP_476432.2	Q5T4W7-1
	ARTN	NM_001136215.2		c.496C>T	p.Arg166Cys	missense	Exon 4 of 4	NP_001129687.1	Q5T4W7-3
	ARTN	NM_057090.3		c.496C>T	p.Arg166Cys	missense	Exon 5 of 5	NP_476431.2	Q5T4W7-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARTN	ENST00000372359.10	TSL:1 MANE Select	c.472C>T	p.Arg158Cys	missense	Exon 5 of 5	ENSP00000361434.5	Q5T4W7-1
	ARTN	ENST00000438616.3	TSL:1	c.523C>T	p.Arg175Cys	missense	Exon 2 of 2	ENSP00000391998.3	Q5T4W7-2
	ARTN	ENST00000498139.6	TSL:1	c.496C>T	p.Arg166Cys	missense	Exon 4 of 4	ENSP00000436727.1	Q5T4W7-3

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152058 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000590 AC: 1 AN: 169606 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000141

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1412698 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 700396

African (AFR) AF: 0.00 AC: 0 AN: 29938

American (AMR) AF: 0.00 AC: 0 AN: 40276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25058

East Asian (EAS) AF: 0.00 AC: 0 AN: 35186

South Asian (SAS) AF: 0.00 AC: 0 AN: 80446

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46974

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4584

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1091860

Other (OTH) AF: 0.00 AC: 0 AN: 58376

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152058 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74266

African (AFR) AF: 0.00 AC: 0 AN: 41436

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5162

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10590

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67974

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.78	D
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Uncertain	0.45	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		4.3
PrimateAI	Pathogenic	0.97	D
PROVEAN	Pathogenic	-6.2	D
REVEL	Pathogenic	0.70
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.020	D
Polyphen		1.0	D
Vest4		0.54
MutPred		0.39		Loss of MoRF binding (P = 0.0054)
MVP		0.93
MPC		3.3
ClinPred		0.97	D
GERP RS		4.1
Varity_R		0.69
gMVP		0.69
Mutation Taster		=24/76	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1459598751; hg19: chr1-44402246;