6-156778031-GTCCTCCTCC-GTCCTCCTCCTCC

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PM4_Supporting BP6_Very_Strong BS1 BS2

The NM_001374828.1(ARID1B):c.370_372dup(p.Ser124dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000392 in 1,532,492 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00034 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00040 (2 hom.)
• Consequence: ARID1B NM_001374828.1 inframe_insertion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.109

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_001374828.1. Strenght limited to Supporting due to length of the change: 1aa.
• BP6: Variant 6-156778031-G-GTCC is Benign according to our data. Variant chr6-156778031-G-GTCC is described in ClinVar as [Likely_benign]. Clinvar id is 588042.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00034 (51/150206) while in subpopulation EAS AF= 0.0028 (14/4994). AF 95% confidence interval is 0.00169. There are 0 homozygotes in gnomad4. There are 28 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd at 48 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARID1B	NM_001374828.1	c.370_372dup	p.Ser124dup	inframe_insertion	1/20	ENST00000636930.2
LOC115308161	NR_163974.1	n.273+214_273+215insGGA		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARID1B	ENST00000636930.2	c.370_372dup	p.Ser124dup	inframe_insertion	1/20	2	NM_001374828.1	A2
	ENST00000603191.2	n.177+214_177+215insGGA		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.000320 AC: 48 AN: 150100 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000268

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000462

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00279

Gnomad SAS AF: 0.00146

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000134

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00114 AC: 121 AN: 106066 Hom.: 0 AF XY: 0.00102 AC XY: 59 AN XY: 57628

Gnomad AFR exome AF: 0.000383

Gnomad AMR exome AF: 0.000985

Gnomad ASJ exome AF: 0.000158

Gnomad EAS exome AF: 0.00544

Gnomad SAS exome AF: 0.00202

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000355

Gnomad OTH exome AF: 0.000606

GnomAD4 exome AF: 0.000398 AC: 550 AN: 1382286 Hom.: 2 Cov.: 35 AF XY: 0.000431 AC XY: 294 AN XY: 681918

Gnomad4 AFR exome AF: 0.000351

Gnomad4 AMR exome AF: 0.000844

Gnomad4 ASJ exome AF: 0.000159

Gnomad4 EAS exome AF: 0.00306

Gnomad4 SAS exome AF: 0.00148

Gnomad4 FIN exome AF: 0.0000280

Gnomad4 NFE exome AF: 0.000233

Gnomad4 OTH exome AF: 0.000450

GnomAD4 genome AF: 0.000340 AC: 51 AN: 150206 Hom.: 0 Cov.: 31 AF XY: 0.000382 AC XY: 28 AN XY: 73360

Gnomad4 AFR AF: 0.000267

Gnomad4 AMR AF: 0.000461

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00280

Gnomad4 SAS AF: 0.00146

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000134

Gnomad4 OTH AF: 0.00144

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 13, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 15, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Sep 25, 2017

- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 30, 2022

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. -

ARID1B-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 27, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs770512547; hg19: chr6-157099165;