Genetic Variant ARIH2:p.Thr423Ser (chr3-48981670-C-G) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_006321.4(ARIH2):c.1268C>G(p.Thr423Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,454 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: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

ARIH2
NM_006321.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.27

Variant links:

Genes affected

ARIH2 (HGNC:690): (ariadne RBR E3 ubiquitin protein ligase 2) The protein encoded by this gene is an E3 ubiquitin-protein ligase that polyubiquitinates some proteins, tagging them for degradation. The encoded protein upregulates p53 in some cancer cells and may inhibit myelopoiesis. Several transcript variants encoding different isoforms have been found for this gene, although the full-length nature of some of them have not been determined yet. [provided by RefSeq, Nov 2015]

ARIH2 links:

ENSG00000235236 (HGNC:):

ENSG00000235236 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.882

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARIH2	NM_006321.4 link	c.1268C>G	p.Thr423Ser	missense_variant	Exon 14 of 16	ENST00000356401.9	NP_006312.1	O95376Q6IBL8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARIH2	ENST00000356401.9 link	c.1268C>G	p.Thr423Ser	missense_variant	Exon 14 of 16	1	NM_006321.4	ENSP00000348769.4		O95376

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461454

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727038

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

9.00e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 10, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1268C>G (p.T423S) alteration is located in exon 14 (coding exon 12) of the ARIH2 gene. This alteration results from a C to G substitution at nucleotide position 1268, causing the threonine (T) at amino acid position 423 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

Pathogenic

0.76

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.29

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.36

T;T

Eigen

Pathogenic

0.91

Eigen_PC

Pathogenic

0.87

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Benign

0.84

.;T

M_CAP

Uncertain

0.16

MetaRNN

Pathogenic

0.88

D;D

MetaSVM

Uncertain

0.74

MutationAssessor

Pathogenic

3.6

H;H

PrimateAI

Pathogenic

0.88

PROVEAN

Uncertain

-3.8

D;D

REVEL

Pathogenic

0.86

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.034

D;D

Polyphen

0.99

D;D

Vest4

0.83

MutPred

0.71

Loss of helix (P = 0.0033);Loss of helix (P = 0.0033);

MVP

0.91

MPC

2.5

ClinPred

0.99

GERP RS

5.7

Varity_R

0.79

gMVP

0.72

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

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over