1-43936385-C-T

Variant names:

• chr1-43936385-C-T
• rs2085096564
• NM_057091.3:c.283C>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_057091.3(ARTN):​c.283C>T​(p.Pro95Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000036 in 1,110,842 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000036 (0 hom.)
• Consequence: ARTN NM_057091.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.09

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10634124).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARTN	NM_057091.3	c.283C>T	p.Pro95Ser	missense_variant	Exon 5 of 5	ENST00000372359.10	NP_476432.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARTN	ENST00000372359.10	c.283C>T	p.Pro95Ser	missense_variant	Exon 5 of 5	1	NM_057091.3	ENSP00000361434.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000360 AC: 4 AN: 1110842 Hom.: 0 Cov.: 31 AF XY: 0.00000377 AC XY: 2 AN XY: 530470

Gnomad4 AFR exome AF: 0.0000890

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000450

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 14, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.307C>T (p.P103S) alteration is located in exon 5 (coding exon 3) of the ARTN gene. This alteration results from a C to T substitution at nucleotide position 307, causing the proline (P) at amino acid position 103 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	.;T;.;T;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0056	N
LIST_S2	Benign	0.39	T;.;.;T;T
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.11	T;T;T;T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.7	.;L;.;L;.
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	0.090	N;N;N;N;N
REVEL	Benign	0.10
Sift	Benign	0.26	T;T;T;T;T
Sift4G	Benign	0.46	T;T;T;T;T
Polyphen		0.0010	B;B;B;B;B
Vest4		0.13
MutPred		0.38		.;Gain of phosphorylation at P95 (P = 0.0011);.;Gain of phosphorylation at P95 (P = 0.0011);.;
MVP		0.62
MPC		2.8
ClinPred		0.086	T
GERP RS		-1.1
Varity_R		0.036
gMVP		0.35

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: rs2085096564; hg19: chr1-44402057;