15-72474747-C-G

Variant names:

• chr15-72474747-C-G
• rs1253333685
• NM_005744.5:c.108C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005744.5(ARIH1):​c.108C>G​(p.Asp36Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000213 in 1,405,466 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D36Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ARIH1 NM_005744.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.403
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08906466).

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.108C>G	p.Asp36Glu	missense	Exon 1 of 14	NP_005735.2	Q9Y4X5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARIH1	ENST00000379887.9	TSL:1 MANE Select	c.108C>G	p.Asp36Glu	missense	Exon 1 of 14	ENSP00000369217.4	Q9Y4X5
	ARIH1	ENST00000915026.1		c.108C>G	p.Asp36Glu	missense	Exon 1 of 14	ENSP00000585085.1
	ARIH1	ENST00000915024.1		c.108C>G	p.Asp36Glu	missense	Exon 1 of 14	ENSP00000585083.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152016 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000972 AC: 2 AN: 205728 AF XY: 0.00000881

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000213 AC: 3 AN: 1405466 Hom.: 0 Cov.: 31 AF XY: 0.00000286 AC XY: 2 AN XY: 699538

African (AFR) AF: 0.00 AC: 0 AN: 29150

American (AMR) AF: 0.00 AC: 0 AN: 37946

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24344

East Asian (EAS) AF: 0.00 AC: 0 AN: 33078

South Asian (SAS) AF: 0.0000374 AC: 3 AN: 80212

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52474

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5598

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1084958

Other (OTH) AF: 0.00 AC: 0 AN: 57706

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000658 AC: 1 AN: 152016 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74242

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

African (AFR) AF: 0.0000241 AC: 1 AN: 41410

American (AMR) AF: 0.00 AC: 0 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10566

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67968

Other (OTH) AF: 0.00 AC: 0 AN: 2088

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	18
DANN	Benign	0.93
DEOGEN2	Benign	0.020	T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.63	T
M_CAP	Pathogenic	0.70	D
MetaRNN	Benign	0.089	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	-0.34	N
PhyloP100		0.40
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-0.59	N
REVEL	Benign	0.29
Sift	Benign	0.64	T
Sift4G	Benign	0.32	T
Polyphen		0.0	B
Vest4		0.29
MutPred		0.079		Loss of loop (P = 0.1242)
MVP		0.52
MPC		1.0
ClinPred		0.19	T
GERP RS		2.9
PromoterAI		-0.040	Neutral
Varity_R		0.11
gMVP		0.040

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1253333685; hg19: chr15-72767088;