Variant 3-48927757-A-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_006321.4(ARIH2):c.199A>C(p.Lys67Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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: 8.69

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3075971).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARIH2	NM_006321.4 linkuse as main transcript	c.199A>C	p.Lys67Gln	missense_variant	3/16	ENST00000356401.9	NP_006312.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARIH2	ENST00000356401.9 linkuse as main transcript	c.199A>C	p.Lys67Gln	missense_variant	3/16	1	NM_006321.4	ENSP00000348769	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000400

AC:

AN:

249918

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135232

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461884

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

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:

0.00

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 15, 2021

The c.199A>C (p.K67Q) alteration is located in exon 3 (coding exon 1) of the ARIH2 gene. This alteration results from a A to C substitution at nucleotide position 199, causing the lysine (K) at amino acid position 67 to be replaced by a glutamine (Q). 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

0.12

BayesDel_addAF

Uncertain

0.10

BayesDel_noAF

Benign

-0.090

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.013

T;T;T;T;T;T

Eigen

Benign

0.14

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

.;D;.;D;D;D

M_CAP

Benign

0.031

MetaRNN

Benign

0.31

T;T;T;T;T;T

MetaSVM

Benign

-0.45

MutationAssessor

Benign

0.69

.;.;N;N;.;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.72

PROVEAN

Benign

-0.67

N;N;N;N;N;D

REVEL

Benign

0.26

Sift

Uncertain

0.020

D;D;T;T;D;D

Sift4G

Benign

0.061

T;D;T;T;T;T

Polyphen

0.87

P;.;B;B;P;.

Vest4

0.48, 0.48

MutPred

0.38

Loss of ubiquitination at K67 (P = 0.0074);Loss of ubiquitination at K67 (P = 0.0074);Loss of ubiquitination at K67 (P = 0.0074);Loss of ubiquitination at K67 (P = 0.0074);Loss of ubiquitination at K67 (P = 0.0074);Loss of ubiquitination at K67 (P = 0.0074);

MVP

0.83

MPC

0.74

ClinPred

0.82

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.26

gMVP

0.14

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over