3-48970698-T-C

Variant names:

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

Variant summary

Our verdict is Likely benign. Variant got -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

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

Verdict is Likely_benign. Variant got -4 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARIH2	NM_006321.4	c.764T>C	p.Val255Ala	missense_variant	Exon 8 of 16	ENST00000356401.9	NP_006312.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARIH2	ENST00000356401.9	c.764T>C	p.Val255Ala	missense_variant	Exon 8 of 16	1	NM_006321.4	ENSP00000348769.4

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 24, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.764T>C (p.V255A) alteration is located in exon 8 (coding exon 6) of the ARIH2 gene. This alteration results from a T to C substitution at nucleotide position 764, causing the valine (V) at amino acid position 255 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

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;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;D
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	0.28	N;N
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	1.0	N;N
REVEL	Uncertain	0.36
Sift	Benign	0.85	T;T
Sift4G	Benign	0.81	T;T
Polyphen		0.017	B;B
Vest4		0.73
MutPred		0.44		Loss of stability (P = 0.0828);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

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

Publications

LitVar

Other links and lift over

dbSNP: rs1355027825; hg19: chr3-49008131;