10-61940340-A-G

Position:

• chr10-61940340-A-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_032199.3(ARID5B):​c.434A>G​(p.Lys145Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000821 in 1,461,862 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: ARID5B NM_032199.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.56

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07070857).
• BS2: High AC in GnomAdExome4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARID5B	NM_032199.3	c.434A>G	p.Lys145Arg	missense_variant	3/10	ENST00000279873.12	NP_115575.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARID5B	ENST00000279873.12	c.434A>G	p.Lys145Arg	missense_variant	3/10	1	NM_032199.3	ENSP00000279873	P3
ARID5B	ENST00000681100.1	c.434A>G	p.Lys145Arg	missense_variant	3/10			ENSP00000506119
ARID5B	ENST00000644638.1	c.434A>G	p.Lys145Arg	missense_variant	3/5			ENSP00000494412

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461862 Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5 AN XY: 727234

Gnomad4 AFR exome AF: 0.000179

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: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Jan 10, 2022

The c.434A>G (p.K145R) alteration is located in exon 3 (coding exon 3) of the ARID5B gene. This alteration results from a A to G substitution at nucleotide position 434, causing the lysine (K) at amino acid position 145 to be replaced by an arginine (R). 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	0.058
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	16
DANN	Benign	0.97
DEOGEN2	Benign	0.066	T;.
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.71	T;T
M_CAP	Benign	0.0021	T
MetaRNN	Benign	0.071	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.34	N;.
MutationTaster	Benign	0.76	N
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	0.18	N;.
REVEL	Benign	0.058
Sift	Benign	0.48	T;.
Sift4G	Benign	0.82	T;.
Polyphen		0.0	B;.
Vest4		0.082
MutPred		0.20		Gain of MoRF binding (P = 0.0698);Gain of MoRF binding (P = 0.0698);
MVP		0.29
MPC		1.4
ClinPred		0.57	D
GERP RS		3.5
Varity_R		0.024
gMVP		0.18

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs959498702; hg19: chr10-63700099;