15-72474873-T-TGGCGGC

Position:

• chr15-72474873-T-TGGCGGC

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_005744.5(ARIH1):​c.252_257dupCGGCGG​(p.Gly85_Gly86dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000565 in 1,413,090 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00047 (0 hom.)
• Consequence: ARIH1 NM_005744.5 disruptive_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2 B:1
• Conservation: PhyloP100: 2.74

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:):

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAd4 at 202 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARIH1	NM_005744.5	c.252_257dupCGGCGG	p.Gly85_Gly86dup	disruptive_inframe_insertion	1/14	ENST00000379887.9	NP_005735.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARIH1	ENST00000379887.9	c.252_257dupCGGCGG	p.Gly85_Gly86dup	disruptive_inframe_insertion	1/14	1	NM_005744.5	ENSP00000369217.4
ARIH1	ENST00000564062.1	c.246_251dupCGGCGG	p.Gly83_Gly84dup	disruptive_inframe_insertion	1/4	3		ENSP00000454774.1
TMEM202-AS1	ENST00000565181.1	n.290_295dupGCCGCC		non_coding_transcript_exon_variant	1/1	6
ARIH1	ENST00000570085.5	n.252_257dupCGGCGG		non_coding_transcript_exon_variant	1/5	3		ENSP00000456746.1

Frequencies

GnomAD3 genomes AF: 0.00133 AC: 199 AN: 149694 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00369

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000730

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000393

Gnomad SAS AF: 0.000642

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000460

Gnomad OTH AF: 0.000977

GnomAD3 exomes AF: 0.000341 AC: 21 AN: 61656 Hom.: 0 AF XY: 0.000232 AC XY: 8 AN XY: 34494

Gnomad AFR exome AF: 0.00389

Gnomad AMR exome AF: 0.00109

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000941

Gnomad FIN exome AF: 0.0000773

Gnomad NFE exome AF: 0.000237

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000473 AC: 597 AN: 1263290 Hom.: 0 Cov.: 30 AF XY: 0.000475 AC XY: 294 AN XY: 619586

Gnomad4 AFR exome AF: 0.00317

Gnomad4 AMR exome AF: 0.000832

Gnomad4 ASJ exome AF: 0.0000494

Gnomad4 EAS exome AF: 0.0000360

Gnomad4 SAS exome AF: 0.000291

Gnomad4 FIN exome AF: 0.0000467

Gnomad4 NFE exome AF: 0.000441

Gnomad4 OTH exome AF: 0.000544

GnomAD4 genome AF: 0.00135 AC: 202 AN: 149800 Hom.: 0 Cov.: 32 AF XY: 0.00134 AC XY: 98 AN XY: 73148

Gnomad4 AFR AF: 0.00375

Gnomad4 AMR AF: 0.000729

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000394

Gnomad4 SAS AF: 0.000643

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000460

Gnomad4 OTH AF: 0.000966

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	This variant, c.252_257dup, results in the insertion of 2 amino acid(s) of the ARIH1 protein (p.Gly89_Gly90dup), but otherwise preserves the integrity of the reading frame. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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. -

ARIH1-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 02, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs375614248; hg19: chr15-72767214;