15-72474716-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_005744.5(ARIH1):c.77A>T(p.Glu26Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E26A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ARIH1 NM_005744.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.58

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

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, ARIH1
• BP4: Computational evidence support a benign effect (MetaRNN=0.3717071).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARIH1	NM_005744.5	c.77A>T	p.Glu26Val	missense_variant	1/14	ENST00000379887.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARIH1	ENST00000379887.9	c.77A>T	p.Glu26Val	missense_variant	1/14	1	NM_005744.5	P1
ARIH1	ENST00000564062.1	c.74A>T	p.Glu25Val	missense_variant	1/4	3
TMEM202-AS1	ENST00000565181.1	n.453T>A		non_coding_transcript_exon_variant	1/1
ARIH1	ENST00000570085.5	c.77A>T	p.Glu26Val	missense_variant, NMD_transcript_variant	1/5	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 11, 2022

The c.77A>T (p.E26V) alteration is located in exon 1 (coding exon 1) of the ARIH1 gene. This alteration results from a A to T substitution at nucleotide position 77, causing the glutamic acid (E) at amino acid position 26 to be replaced by a valine (V). 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	0.13
BayesDel_addAF	Uncertain	0.015	T
BayesDel_noAF	Benign	-0.22
Cadd	Uncertain	24
Dann	Benign	0.94
DEOGEN2	Benign	0.015	T
Eigen	Benign	-0.083
Eigen_PC	Benign	0.013
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.73	T
M_CAP	Pathogenic	0.96	D
MetaRNN	Benign	0.37	T
MetaSVM	Benign	-0.35	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	0.54	D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.49	N
REVEL	Benign	0.28
Sift	Benign	1.0	T
Sift4G	Benign	0.23	T
Polyphen		0.82	P
Vest4		0.40
MutPred		0.20		Loss of solvent accessibility (P = 0.0509);
MVP		0.74
MPC		1.2
ClinPred		0.46	T
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.26
gMVP		0.11

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-72767057;