10-61902274-G-A

Position:

• chr10-61902274-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_032199.3(ARID5B):​c.137G>A​(p.Cys46Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: ARID5B NM_032199.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.76

Genes affected

ARID5B (HGNC:17362): (AT-rich interaction domain 5B) This gene encodes a member of the AT-rich interaction domain (ARID) family of DNA binding proteins. The encoded protein forms a histone H3K9Me2 demethylase complex with PHD finger protein 2 and regulates the transcription of target genes involved in adipogenesis and liver development. This gene also plays a role in cell growth and differentiation of B-lymphocyte progenitors, and single nucleotide polymorphisms in this gene are associated with acute lymphoblastic leukemia. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Sep 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.833

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARID5B	NM_032199.3	c.137G>A	p.Cys46Tyr	missense_variant	2/10	ENST00000279873.12	NP_115575.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARID5B	ENST00000279873.12	c.137G>A	p.Cys46Tyr	missense_variant	2/10	1	NM_032199.3	ENSP00000279873	P3
ARID5B	ENST00000681100.1	c.137G>A	p.Cys46Tyr	missense_variant	2/10			ENSP00000506119
ARID5B	ENST00000644638.1	c.137G>A	p.Cys46Tyr	missense_variant	2/5			ENSP00000494412

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

ARID5B-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 05, 2022

The ARID5B c.137G>A variant is predicted to result in the amino acid substitution p.Cys46Tyr. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	T;.
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Benign	0.021	T
MetaRNN	Pathogenic	0.83	D;D
MetaSVM	Benign	-0.55	T
MutationAssessor	Uncertain	2.1	M;.
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-2.0	N;.
REVEL	Uncertain	0.35
Sift	Uncertain	0.0010	D;.
Sift4G	Uncertain	0.0060	D;.
Polyphen		1.0	D;.
Vest4		0.86
MutPred		0.71		Gain of catalytic residue at C46 (P = 0.0248);Gain of catalytic residue at C46 (P = 0.0248);
MVP		0.62
MPC		2.1
ClinPred		0.97	D
GERP RS		5.8
Varity_R		0.84
gMVP		0.84

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1053149301; hg19: chr10-63662033;