Genetic Variant ARID1B:p.Gln578Lys (chr6-156779412-C-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_001374828.1(ARID1B):c.1732C>A(p.Gln578Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000000762 in 1,312,740 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 7.6e-7 ( 0 hom. )

Consequence

ARID1B
NM_001374828.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.27

Publications

0 publications found

Variant links:

Genes affected

ARID1B (HGNC:18040): (AT-rich interaction domain 1B) This locus encodes an AT-rich DNA interacting domain-containing protein. The encoded protein is a component of the SWI/SNF chromatin remodeling complex and may play a role in cell-cycle activation. The protein encoded by this locus is similar to AT-rich interactive domain-containing protein 1A. These two proteins function as alternative, mutually exclusive ARID-subunits of the SWI/SNF complex. The associated complexes play opposing roles. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2016]

ARID1B Gene-Disease associations (from GenCC):

Coffin-Siris syndrome
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, Illumina, ClinGen
Coffin-Siris syndrome 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics

ARID1B links:

ENSG00000296922 (HGNC:):

ENSG00000296922 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.26568985).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARID1B	NM_001374828.1 link	c.1732C>A	p.Gln578Lys	missense_variant	Exon 1 of 20	ENST00000636930.2	NP_001361757.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARID1B	ENST00000636930.2 link	c.1732C>A	p.Gln578Lys	missense_variant	Exon 1 of 20	2	NM_001374828.1	ENSP00000490491.2		Q8NFD5-3A0A6Q8NVI4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.62e-7

AC:

AN:

1312740

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

653162

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

27082

American (AMR)

AF:

0.00

AC:

AN:

32218

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21790

East Asian (EAS)

AF:

0.00

AC:

AN:

29050

South Asian (SAS)

AF:

0.00

AC:

AN:

74738

European-Finnish (FIN)

AF:

0.00

AC:

AN:

32922

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4770

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1038040

Other (OTH)

AF:

0.0000192

AC:

AN:

52130

⚠️ 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: 0.275

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

Uncertain

0.46

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.55

CADD

Uncertain

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.025

.;T;.;.;.;.

Eigen

Benign

-0.093

Eigen_PC

Benign

-0.067

FATHMM_MKL

Benign

0.67

LIST_S2

Benign

0.76

T;T;T;T;T;T

M_CAP

Pathogenic

0.54

MetaRNN

Benign

0.27

T;T;T;T;T;T

MetaSVM

Benign

-0.81

MutationAssessor

Benign

1.6

.;L;L;L;.;.

PhyloP100

6.3

PrimateAI

Pathogenic

0.92

PROVEAN

Uncertain

-2.9

D;N;.;.;.;.

REVEL

Benign

0.14

Sift

Pathogenic

0.0

D;T;.;.;.;.

Sift4G

Benign

0.53

.;T;.;.;.;.

Polyphen

0.61, 0.73

.;P;.;P;.;.

Vest4

0.21

MutPred

0.34

.;Gain of methylation at Q495 (P = 1e-04);Gain of methylation at Q495 (P = 1e-04);Gain of methylation at Q495 (P = 1e-04);.;.;

MVP

0.44

MPC

0.82

ClinPred

0.89

GERP RS

3.0

PromoterAI

-0.11

Neutral

(source)

Varity_R

0.31

gMVP

0.23

Mutation Taster

=74/26

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