Genetic Variant ARID1B:p.Gly1572Ser (chr6-157200939-G-A) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_ModerateBP6BS1BS2_Supporting

The NM_001438482.1(ARID1B):c.4843G>A(p.Gly1615Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000607 in 1,613,816 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1615R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000064 ( 0 hom. )

Consequence

ARID1B
NM_001438482.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 4.28

Publications

4 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.14807618).

BP6

Variant 6-157200939-G-A is Benign according to our data. Variant chr6-157200939-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 434361.

BS1

Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.0000636 (93/1461612) while in subpopulation EAS AF = 0.000327 (13/39698). AF 95% confidence interval is 0.000193. There are 0 homozygotes in GnomAdExome4. There are 44 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High AC in GnomAd4 at 5 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001438482.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ARID1B	NM_001374828.1	MANE Select	c.4714G>A	p.Gly1572Ser	missense	Exon 18 of 20	NP_001361757.1
ARID1B	NM_001438482.1		c.4843G>A	p.Gly1615Ser	missense	Exon 19 of 21	NP_001425411.1
ARID1B	NM_001438483.1		c.4756G>A	p.Gly1586Ser	missense	Exon 19 of 21	NP_001425412.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ARID1B	ENST00000636930.2	TSL:2 MANE Select	c.4714G>A	p.Gly1572Ser	missense	Exon 18 of 20	ENSP00000490491.2
ARID1B	ENST00000346085.10	TSL:1	c.4594G>A	p.Gly1532Ser	missense	Exon 19 of 21	ENSP00000344546.5
ARID1B	ENST00000350026.11	TSL:1	c.4555G>A	p.Gly1519Ser	missense	Exon 17 of 19	ENSP00000055163.8

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000759

AC:

AN:

250166

AF XY:

0.0000665

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000869

Gnomad ASJ exome

AF:

0.000300

Gnomad EAS exome

AF:

0.000272

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000708

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000636

AC:

AN:

1461612

Hom.:

Cov.:

AF XY:

0.0000605

AC XY:

AN XY:

727098

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33480

American (AMR)

AF:

0.0000671

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.000191

AC:

AN:

26116

East Asian (EAS)

AF:

0.000327

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86242

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53258

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000585

AC:

AN:

1111950

Other (OTH)

AF:

0.0000994

AC:

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152204

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74358

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41460

American (AMR)

AF:

0.0000654

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3472

East Asian (EAS)

AF:

0.000192

AC:

AN:

5202

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68018

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000601

Hom.:

Bravo

AF:

0.0000264

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000906

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Coffin-Siris syndrome 1 (1)

Inborn genetic diseases (1)

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.27

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.039

Eigen

Uncertain

0.40

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.90

M_CAP

Benign

0.011

MetaRNN

Benign

0.15

MetaSVM

Benign

-0.79

MutationAssessor

Benign

1.7

PhyloP100

4.3

PrimateAI

Benign

0.42

PROVEAN

Benign

-1.2

REVEL

Benign

0.22

Sift

Benign

0.11

Sift4G

Benign

0.40

Polyphen

0.92

Vest4

0.44

MVP

0.45

MPC

1.5

ClinPred

0.078

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.16

gMVP

0.43

Mutation Taster

=79/21

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over