rs34786733

chr6-157167056-G-Achr6-157167056-G-Cchr6-157167056-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001374828.1(ARID1B):c.3106G>A(p.Gly1036Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000993 in 1,611,808 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1036R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0055 (7 hom., cov: 33)
  • Exomes 𝑓: 0.00052 (1 hom.)
• Consequence: ARID1B NM_001374828.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 3.77

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003992349).
• BP6: Variant 6-157167056-G-A is Benign according to our data. Variant chr6-157167056-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 126323.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-157167056-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00551 (839/152302) while in subpopulation AFR AF= 0.0189 (787/41568). AF 95% confidence interval is 0.0178. There are 7 homozygotes in gnomad4. There are 378 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 839 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARID1B	NM_001374828.1	c.3106G>A	p.Gly1036Ser	missense_variant	9/20	ENST00000636930.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARID1B	ENST00000636930.2	c.3106G>A	p.Gly1036Ser	missense_variant	9/20	2	NM_001374828.1	A2

Frequencies

GnomAD3 genomes AF: 0.00551 AC: 839 AN: 152184 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.0190

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00249

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00147 AC: 366 AN: 249620 Hom.: 3 AF XY: 0.00114 AC XY: 154 AN XY: 135046

Gnomad AFR exome AF: 0.0185

Gnomad AMR exome AF: 0.00139

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000793

Gnomad OTH exome AF: 0.000980

GnomAD4 exome AF: 0.000521 AC: 761 AN: 1459506 Hom.: 1 Cov.: 30 AF XY: 0.000432 AC XY: 314 AN XY: 726186

Gnomad4 AFR exome AF: 0.0178

Gnomad4 AMR exome AF: 0.00139

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000369

Gnomad4 OTH exome AF: 0.000961

GnomAD4 genome AF: 0.00551 AC: 839 AN: 152302 Hom.: 7 Cov.: 33 AF XY: 0.00508 AC XY: 378 AN XY: 74464

Gnomad4 AFR AF: 0.0189

Gnomad4 AMR AF: 0.00248

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000970 Hom.: 1

Bravo AF: 0.00609

ESP6500AA AF: 0.0157 AC: 69

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00180 AC: 219

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 14, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 02, 2022	See Variant Classification Assertion Criteria. -

not specified Benign:1

Likely benign, no assertion criteria provided

clinical testing

Genetic Services Laboratory, University of Chicago

-

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 16, 2017

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Coffin-Siris syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.59
Cadd	Benign	22
Dann	Benign	0.97
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.42
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.59	T;T;T;T;T;T;T;T;T;T;T
MetaRNN	Benign	0.0040	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.84	D;D;D;D
PrimateAI	Benign	0.45	T
REVEL	Benign	0.064
Polyphen		0.29, 0.20, 0.13	.;B;.;B;.;.;.;.;B;.;.
Vest4		0.092
MVP		0.34
MPC		0.31
ClinPred		0.012	T
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.046
gMVP		0.23

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs34786733; hg19: chr6-157488190;