chr15-72474873-T-TGGCGGC

Variant names:

• chr15-72474873-T-TGGCGGC
• rs375614248
• NM_005744.5:c.252_257dupCGGCGG

Variant summary

Our verdict is Likely benign. The variant received -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 (★★). Synonymous variant affecting the same amino acid position (i.e. G86G) has been classified as Likely benign.

• 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
• Publications: 1 publications found

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

Our verdict: Likely_benign. The variant received -4 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005744.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARIH1	NM_005744.5	MANE Select	c.252_257dupCGGCGG	p.Gly85_Gly86dup	disruptive_inframe_insertion	Exon 1 of 14	NP_005735.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARIH1	ENST00000379887.9	TSL:1 MANE Select	c.252_257dupCGGCGG	p.Gly85_Gly86dup	disruptive_inframe_insertion	Exon 1 of 14	ENSP00000369217.4
	ARIH1	ENST00000915026.1		c.252_257dupCGGCGG	p.Gly85_Gly86dup	disruptive_inframe_insertion	Exon 1 of 14	ENSP00000585085.1
	ARIH1	ENST00000915024.1		c.252_257dupCGGCGG	p.Gly85_Gly86dup	disruptive_inframe_insertion	Exon 1 of 14	ENSP00000585083.1

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

GnomAD2 exomes AF: 0.000341 AC: 21 AN: 61656 AF XY: 0.000232

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 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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00317 AC: 83 AN: 26220

American (AMR) AF: 0.000832 AC: 18 AN: 21622

Ashkenazi Jewish (ASJ) AF: 0.0000494 AC: 1 AN: 20236

East Asian (EAS) AF: 0.0000360 AC: 1 AN: 27798

South Asian (SAS) AF: 0.000291 AC: 17 AN: 58512

European-Finnish (FIN) AF: 0.0000467 AC: 2 AN: 42788

Middle Eastern (MID) AF: 0.000401 AC: 2 AN: 4986

European-Non Finnish (NFE) AF: 0.000441 AC: 445 AN: 1009624

Other (OTH) AF: 0.000544 AC: 28 AN: 51504

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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

African (AFR) AF: 0.00375 AC: 153 AN: 40764

American (AMR) AF: 0.000729 AC: 11 AN: 15092

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3442

East Asian (EAS) AF: 0.000394 AC: 2 AN: 5076

South Asian (SAS) AF: 0.000643 AC: 3 AN: 4666

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10174

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.000460 AC: 31 AN: 67336

Other (OTH) AF: 0.000966 AC: 2 AN: 2070

Alfa AF: 0.00 Hom.: 24

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	-	1	ARIH1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.7
Mutation Taster		=82/18	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs375614248; hg19: chr15-72767214; COSMIC: COSV65910834;