15-72474723-G-C

Position:

chr15-72474723-G-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_005744.5(ARIH1):c.84G>C(p.Glu28Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000997 in 1,564,734 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: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

ARIH1
NM_005744.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.721

Variant links:

Genes affected

ARIH1 (HGNC:689): (ariadne RBR E3 ubiquitin protein ligase 1) Enables enzyme binding activity; ubiquitin-protein transferase activity; and zinc ion binding activity. Involved in protein ubiquitination. Located in Lewy body; cytoplasm; and nuclear body. Colocalizes with cullin-RING ubiquitin ligase complex. [provided by Alliance of Genome Resources, Apr 2022]

ARIH1 links:

TMEM202-AS1 (HGNC:53265): (TMEM202 antisense RNA 1)

TMEM202-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.016627043).

BS2

High AC in GnomAdExome4 at 153 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARIH1	NM_005744.5 link	c.84G>C	p.Glu28Asp	missense_variant	1/14	ENST00000379887.9	NP_005735.2	Q9Y4X5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
ARIH1	ENST00000379887.9 link	c.84G>C	p.Glu28Asp	missense_variant	1/14	1	NM_005744.5	ENSP00000369217.4	Q9Y4X5
ARIH1	ENST00000564062.1 link	c.78G>C	p.Glu26Asp	missense_variant	1/4	3		ENSP00000454774.1	H3BNB9
TMEM202-AS1	ENST00000565181.1 link	n.446C>G		non_coding_transcript_exon_variant	1/1	6
ARIH1	ENST00000570085.5 link	n.84G>C		non_coding_transcript_exon_variant	1/5	3		ENSP00000456746.1	H3BSK4

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152058

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000134

AC:

AN:

208682

Hom.:

AF XY:

0.0000957

AC XY:

AN XY:

114986

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00169

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000478

Gnomad NFE exome

AF:

0.0000627

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000108

AC:

153

AN:

1412676

Hom.:

Cov.:

AF XY:

0.0000996

AC XY:

AN XY:

703070

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00406

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000381

Gnomad4 NFE exome

AF:

0.0000110

Gnomad4 OTH exome

AF:

0.0000344

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152058

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74276

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000385

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ExAC

AF:

0.000182

AC:

Asia WGS

AF:

0.00118

AC:

AN:

3408

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 09, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 28 of the ARIH1 protein (p.Glu28Asp). This variant is present in population databases (rs773605993, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with ARIH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1379147). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.060

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.30

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.014

Eigen

Benign

-0.38

Eigen_PC

Benign

-0.27

FATHMM_MKL

Benign

0.24

LIST_S2

Benign

0.64

M_CAP

Pathogenic

0.73

MetaRNN

Benign

0.017

MetaSVM

Benign

-0.73

MutationAssessor

Benign

0.0

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

0.48

REVEL

Benign

0.17

Sift

Pathogenic

0.0

Sift4G

Benign

0.75

Polyphen

0.27

Vest4

0.14

MutPred

0.14

Loss of helix (P = 0.0821);

MVP

0.62

MPC

0.97

ClinPred

0.22

GERP RS

1.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.34

gMVP

0.056

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