Genetic Variant ARID1B:p.Arg1198Gly (chr6-157181056-C-G) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate

The NM_001374828.1(ARID1B):c.3592C>G(p.Arg1198Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. R1198Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

ARID1B
NM_001374828.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.12

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

ARID1B links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_001374828.1

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.862

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001374828.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ARID1B	NM_001374828.1	MANE Select	c.3592C>G	p.Arg1198Gly	missense	Exon 12 of 20	NP_001361757.1	A0A6Q8NVI4
ARID1B	NM_001438482.1		c.3721C>G	p.Arg1241Gly	missense	Exon 13 of 21	NP_001425411.1
ARID1B	NM_001438483.1		c.3634C>G	p.Arg1212Gly	missense	Exon 13 of 21	NP_001425412.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ARID1B	ENST00000636930.2	TSL:2 MANE Select	c.3592C>G	p.Arg1198Gly	missense	Exon 12 of 20	ENSP00000490491.2	A0A6Q8NVI4
ARID1B	ENST00000346085.10	TSL:1	c.3472C>G	p.Arg1158Gly	missense	Exon 13 of 21	ENSP00000344546.5	A0A3F2YNW7
ARID1B	ENST00000350026.11	TSL:1	c.3433C>G	p.Arg1145Gly	missense	Exon 11 of 19	ENSP00000055163.8	Q8NFD5-5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.20

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.27

Eigen

Uncertain

0.46

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Uncertain

0.91

LIST_S2

Pathogenic

0.99

M_CAP

Benign

0.059

MetaRNN

Pathogenic

0.86

MetaSVM

Benign

-0.45

MutationAssessor

Uncertain

2.1

PhyloP100

4.1

PrimateAI

Uncertain

0.74

PROVEAN

Pathogenic

-5.3

REVEL

Uncertain

0.60

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.024

Polyphen

1.0

Vest4

0.91

MutPred

0.77

Loss of helix (P = 0.0237)

MVP

0.83

MPC

1.1

ClinPred

0.99

GERP RS

2.6

Varity_R

0.96

gMVP

0.69

Mutation Taster

=30/70

disease causing

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over