Genetic Variant NM_005744.5:c.246_257dupCGGCGGCGGCGG (chr15-72474873-T-TGGCGGCGGCGGC) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_005744.5(ARIH1):c.246_257dupCGGCGGCGGCGG(p.Gly83_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 0.00000425 in 1,413,008 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. 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 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000032 ( 0 hom. )

Consequence

ARIH1
NM_005744.5 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.74

Publications

1 publications found

Variant links:

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]

ARIH1 links:

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

TMEM202-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

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.246_257dupCGGCGGCGGCGG	p.Gly83_Gly86dup	disruptive_inframe_insertion	Exon 1 of 14	NP_005735.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ARIH1	ENST00000379887.9	TSL:1 MANE Select	c.246_257dupCGGCGGCGGCGG	p.Gly83_Gly86dup	disruptive_inframe_insertion	Exon 1 of 14	ENSP00000369217.4
ARIH1	ENST00000915026.1		c.246_257dupCGGCGGCGGCGG	p.Gly83_Gly86dup	disruptive_inframe_insertion	Exon 1 of 14	ENSP00000585085.1
ARIH1	ENST00000915024.1		c.246_257dupCGGCGGCGGCGG	p.Gly83_Gly86dup	disruptive_inframe_insertion	Exon 1 of 14	ENSP00000585083.1

Frequencies

GnomAD3 genomes

AF:

0.0000134

AC:

AN:

149696

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000663

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000148

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000317

AC:

AN:

1263312

Hom.:

Cov.:

AF XY:

0.00000484

AC XY:

AN XY:

619602

show subpopulations

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

African (AFR)

AF:

0.0000381

AC:

AN:

26224

American (AMR)

AF:

0.00

AC:

AN:

21626

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20236

East Asian (EAS)

AF:

0.00

AC:

AN:

27798

South Asian (SAS)

AF:

0.00

AC:

AN:

58512

European-Finnish (FIN)

AF:

0.00

AC:

AN:

42788

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4986

European-Non Finnish (NFE)

AF:

9.90e-7

AC:

AN:

1009636

Other (OTH)

AF:

0.0000388

AC:

AN:

51506

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000000000310862), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.287

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000134

AC:

AN:

149696

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73034

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

40650

American (AMR)

AF:

0.0000663

AC:

AN:

15074

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3442

East Asian (EAS)

AF:

0.00

AC:

AN:

5092

South Asian (SAS)

AF:

0.00

AC:

AN:

4670

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10174

Middle Eastern (MID)

AF:

0.00

AC:

AN:

310

European-Non Finnish (NFE)

AF:

0.0000148

AC:

AN:

67346

Other (OTH)

AF:

0.00

AC:

AN:

2048

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.675

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.7

Mutation Taster

=82/18

polymorphism

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over