Genetic Variant ARID3A:p.Glu50Asp (chr19-929678-G-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_005224.3(ARID3A):c.150G>C(p.Glu50Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000712 in 1,404,650 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E50K) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

ARID3A
NM_005224.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.174

Publications

0 publications found

Variant links:

Genes affected

ARID3A (HGNC:3031): (AT-rich interaction domain 3A) This gene encodes a member of the ARID (AT-rich interaction domain) family of DNA binding proteins. It was found by homology to the Drosophila dead ringer gene, which is important for normal embryogenesis. Other ARID family members have roles in embryonic patterning, cell lineage gene regulation, cell cycle control, transcriptional regulation, and possibly in chromatin structure modification. [provided by RefSeq, Jul 2008]

ARID3A links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0673691).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARID3A	NM_005224.3 link	c.150G>C	p.Glu50Asp	missense_variant	Exon 2 of 9	ENST00000263620.8	NP_005215.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARID3A	ENST00000263620.8 link	c.150G>C	p.Glu50Asp	missense_variant	Exon 2 of 9	1	NM_005224.3	ENSP00000263620.2
ARID3A	ENST00000585895.1 link	n.*180G>C		downstream_gene_variant		2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.12e-7

AC:

AN:

1404650

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

695140

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000306

AC:

AN:

32718

American (AMR)

AF:

0.00

AC:

AN:

38032

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25288

East Asian (EAS)

AF:

0.00

AC:

AN:

37562

South Asian (SAS)

AF:

0.00

AC:

AN:

81020

European-Finnish (FIN)

AF:

0.00

AC:

AN:

35100

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4684

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1091660

Other (OTH)

AF:

0.00

AC:

AN:

58586

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.65

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.076

Eigen

Benign

-0.66

Eigen_PC

Benign

-0.62

FATHMM_MKL

Benign

0.46

LIST_S2

Benign

0.45

M_CAP

Benign

0.054

MetaRNN

Benign

0.067

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.8

PhyloP100

0.17

PrimateAI

Pathogenic

0.89

PROVEAN

Benign

-0.93

REVEL

Benign

0.032

Sift

Benign

0.082

Sift4G

Benign

0.30

Polyphen

0.0010

Vest4

0.049

MutPred

0.13

Loss of helix (P = 0.0376);

MVP

0.41

MPC

0.14

ClinPred

0.066

GERP RS

1.1

Varity_R

0.15

gMVP

0.17

Mutation Taster

=93/7

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over