15-72474829-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_005744.5(ARIH1):c.190G>A(p.Gly64Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G64A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ARIH1 NM_005744.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.62

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 2 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=0.31265914).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARIH1	NM_005744.5	c.190G>A	p.Gly64Arg	missense_variant	1/14	ENST00000379887.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARIH1	ENST00000379887.9	c.190G>A	p.Gly64Arg	missense_variant	1/14	1	NM_005744.5	P1
ARIH1	ENST00000564062.1	c.187G>A	p.Gly63Arg	missense_variant	1/4	3
TMEM202-AS1	ENST00000565181.1	n.340C>T		non_coding_transcript_exon_variant	1/1
ARIH1	ENST00000570085.5	c.190G>A	p.Gly64Arg	missense_variant, NMD_transcript_variant	1/5	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1255980 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 615988

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	ARIH1: PM2, PP2, PP3 -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Nov 17, 2023	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 64 of the ARIH1 protein (p.Gly64Arg). 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	0.30
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.023	T
Eigen	Benign	0.028
Eigen_PC	Benign	0.12
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.82	T
M_CAP	Pathogenic	0.90	D
MetaRNN	Benign	0.31	T
MetaSVM	Uncertain	0.37	D
MutationAssessor	Benign	0.55	N
MutationTaster	Benign	0.99	D
PrimateAI	Pathogenic	0.97	D
PROVEAN	Benign	0.38	N
REVEL	Uncertain	0.37
Sift	Benign	0.10	T
Sift4G	Benign	0.47	T
Polyphen		0.95	P
Vest4		0.27
MutPred		0.30		Gain of sheet (P = 0.0827);
MVP		0.51
MPC		1.3
ClinPred		0.82	D
GERP RS		3.8
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		4.1
Varity_R		0.15
gMVP		0.34

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: chr15-72767170;