15-72474797-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_005744.5(ARIH1):c.158G>A(p.Gly53Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00000222 in 1,349,356 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: 0.0000022 (0 hom.)
• Consequence: ARIH1 NM_005744.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.20

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, ARIH1
• BP4: Computational evidence support a benign effect (MetaRNN=0.21361911).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARIH1	NM_005744.5	c.158G>A	p.Gly53Asp	missense_variant	1/14	ENST00000379887.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARIH1	ENST00000379887.9	c.158G>A	p.Gly53Asp	missense_variant	1/14	1	NM_005744.5	P1
ARIH1	ENST00000564062.1	c.155G>A	p.Gly52Asp	missense_variant	1/4	3
TMEM202-AS1	ENST00000565181.1	n.372C>T		non_coding_transcript_exon_variant	1/1
ARIH1	ENST00000570085.5	c.158G>A	p.Gly53Asp	missense_variant, NMD_transcript_variant	1/5	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000222 AC: 3 AN: 1349356 Hom.: 0 Cov.: 31 AF XY: 0.00000299 AC XY: 2 AN XY: 668960

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: 0.00000285

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Dec 18, 2023

This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 53 of the ARIH1 protein (p.Gly53Asp). 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	0.16
BayesDel_addAF	Uncertain	0.073	D
BayesDel_noAF	Benign	-0.13
Cadd	Pathogenic	26
Dann	Uncertain	0.99
DEOGEN2	Benign	0.015	T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.095
FATHMM_MKL	Benign	0.35	N
LIST_S2	Benign	0.75	T
M_CAP	Pathogenic	0.95	D
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.30	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	0.94	N
PrimateAI	Pathogenic	0.95	D
PROVEAN	Benign	0.74	N
REVEL	Benign	0.22
Sift	Uncertain	0.018	D
Sift4G	Benign	0.53	T
Polyphen		0.38	B
Vest4		0.20
MutPred		0.25		Gain of solvent accessibility (P = 0.0638);
MVP		0.29
MPC		1.4
ClinPred		0.51	D
GERP RS		3.9
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		3.9
Varity_R		0.30
gMVP		0.36

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-72767138;