15-72474699-G-C

Position:

• chr15-72474699-G-C

Variant summary

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

The NM_005744.5(ARIH1):​c.60G>C​(p.Glu20Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: 33)
• Consequence: ARIH1 NM_005744.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.18

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]

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

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=0.1521931).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARIH1	NM_005744.5	c.60G>C	p.Glu20Asp	missense_variant	1/14	ENST00000379887.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARIH1	ENST00000379887.9	c.60G>C	p.Glu20Asp	missense_variant	1/14	1	NM_005744.5	P1
ARIH1	ENST00000564062.1	c.57G>C	p.Glu19Asp	missense_variant	1/4	3
TMEM202-AS1	ENST00000565181.1	n.470C>G		non_coding_transcript_exon_variant	1/1
ARIH1	ENST00000570085.5	c.60G>C	p.Glu20Asp	missense_variant, NMD_transcript_variant	1/5	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 17, 2023

This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 20 of the ARIH1 protein (p.Glu20Asp). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ARIH1-related conditions. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0099	T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.66	T
M_CAP	Pathogenic	0.89	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	-0.34	N
MutationTaster	Benign	0.76	N
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	0.35	N
REVEL	Benign	0.25
Sift	Benign	0.28	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.20
MutPred		0.085		Loss of stability (P = 0.2078);
MVP		0.48
MPC		0.97
ClinPred		0.34	T
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.26
gMVP		0.016

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: rs1316007172; hg19: chr15-72767040;