chr3-48970698-T-C

Variant names:

• chr3-48970698-T-C
• rs1355027825
• NM_006321.4:c.764T>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_006321.4(ARIH2):​c.764T>C​(p.Val255Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,461,068 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: ARIH2 NM_006321.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.63
• Publications: 1 publications found

Genes affected

ARIH2 (HGNC:690): (ariadne RBR E3 ubiquitin protein ligase 2) The protein encoded by this gene is an E3 ubiquitin-protein ligase that polyubiquitinates some proteins, tagging them for degradation. The encoded protein upregulates p53 in some cancer cells and may inhibit myelopoiesis. Several transcript variants encoding different isoforms have been found for this gene, although the full-length nature of some of them have not been determined yet. [provided by RefSeq, Nov 2015]

ACMG classification

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

• BS2: High AC in GnomAdExome4 at 6 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006321.4. 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
	ARIH2	NM_006321.4	MANE Select	c.764T>C	p.Val255Ala	missense	Exon 8 of 16	NP_006312.1	Q6IBL8
	ARIH2	NM_001349213.2		c.764T>C	p.Val255Ala	missense	Exon 9 of 17	NP_001336142.1
	ARIH2	NM_001349214.2		c.764T>C	p.Val255Ala	missense	Exon 8 of 16	NP_001336143.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARIH2	ENST00000356401.9	TSL:1 MANE Select	c.764T>C	p.Val255Ala	missense	Exon 8 of 16	ENSP00000348769.4	O95376
	ARIH2	ENST00000449376.5	TSL:1	c.764T>C	p.Val255Ala	missense	Exon 9 of 17	ENSP00000403222.1	O95376
	ARIH2	ENST00000972221.1		c.764T>C	p.Val255Ala	missense	Exon 9 of 18	ENSP00000642280.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1461068 Hom.: 0 Cov.: 29 AF XY: 0.00000413 AC XY: 3 AN XY: 726872

African (AFR) AF: 0.00 AC: 0 AN: 33456

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53368

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1111342

Other (OTH) AF: 0.00 AC: 0 AN: 60360

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Uncertain	0.052	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	23
DANN	Benign	0.89
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.15
Eigen_PC	Benign	0.086
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.053	D
MetaRNN	Uncertain	0.55	D
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	0.28	N
PhyloP100		7.6
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	1.0	N
REVEL	Uncertain	0.36
Sift	Benign	0.85	T
Sift4G	Benign	0.81	T
Polyphen		0.017	B
Vest4		0.73
MutPred		0.44		Loss of stability (P = 0.0828)
MVP		0.71
MPC		2.5
ClinPred		0.72	D
GERP RS		5.4
Varity_R		0.12
gMVP		0.47
Mutation Taster		=53/47	polymorphism

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: rs1355027825; hg19: chr3-49008131;