Genetic Variant NM_057091.3:c.182C>A (chr1-43936214-C-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_057091.3(ARTN):c.182C>A(p.Pro61His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000751 in 1,331,180 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P61L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.5e-7 ( 0 hom. )

Consequence

ARTN
NM_057091.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.579

Publications

0 publications found

Variant links:

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]

ARTN links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3636999).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ARTN	NM_057091.3	MANE Select	c.182C>A	p.Pro61His	missense	Exon 4 of 5	NP_476432.2	Q5T4W7-1
ARTN	NM_001136215.2		c.206C>A	p.Pro69His	missense	Exon 3 of 4	NP_001129687.1	Q5T4W7-3
ARTN	NM_057090.3		c.206C>A	p.Pro69His	missense	Exon 4 of 5	NP_476431.2	Q5T4W7-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ARTN	ENST00000372359.10	TSL:1 MANE Select	c.182C>A	p.Pro61His	missense	Exon 4 of 5	ENSP00000361434.5	Q5T4W7-1
ARTN	ENST00000438616.3	TSL:1	c.233C>A	p.Pro78His	missense	Exon 1 of 2	ENSP00000391998.3	Q5T4W7-2
ARTN	ENST00000498139.6	TSL:1	c.206C>A	p.Pro69His	missense	Exon 3 of 4	ENSP00000436727.1	Q5T4W7-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.51e-7

AC:

AN:

1331180

Hom.:

Cov.:

AF XY:

0.00000153

AC XY:

AN XY:

654182

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

27734

American (AMR)

AF:

0.00

AC:

AN:

27950

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21784

East Asian (EAS)

AF:

0.0000302

AC:

AN:

33154

South Asian (SAS)

AF:

0.00

AC:

AN:

71152

European-Finnish (FIN)

AF:

0.00

AC:

AN:

32424

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4010

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1057626

Other (OTH)

AF:

0.00

AC:

AN:

55346

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.025

BayesDel_noAF

Benign

-0.27

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.14

Eigen

Benign

-0.50

Eigen_PC

Benign

-0.66

FATHMM_MKL

Benign

0.068

LIST_S2

Benign

0.48

M_CAP

Pathogenic

0.91

MetaRNN

Benign

0.36

MetaSVM

Uncertain

-0.25

MutationAssessor

Benign

1.8

PhyloP100

-0.58

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-1.3

REVEL

Benign

0.19

Sift

Uncertain

0.0060

Sift4G

Benign

0.61

Polyphen

1.0

Vest4

0.17

MutPred

0.17

Gain of solvent accessibility (P = 0.0156)

MVP

0.93

MPC

1.7

ClinPred

0.61

GERP RS

1.6

PromoterAI

-0.020

Neutral

(source)

Varity_R

0.069

gMVP

0.21

Mutation Taster

=91/9

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over