6-156778031-GTCCTCCTCC-GTCCTCC

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PM4_Supporting BP6 BS1 BS2

The NM_001374828.1(ARID1B):c.370_372del(p.Ser124del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000403 in 1,482,920 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00019 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00043 (0 hom.)
• Consequence: ARID1B NM_001374828.1 inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 1.30

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 -8 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-GTCC-G is Benign according to our data. Variant chr6-156778031-GTCC-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 210267.We mark this variant Likely_benign, oryginal submissions are: {Benign=4, Uncertain_significance=1}. Variant chr6-156778031-GTCC-G is described in Lovd as [Benign]. Variant chr6-156778031-GTCC-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.000428 (570/1332780) while in subpopulation AMR AF= 0.00154 (51/33120). AF 95% confidence interval is 0.0012. There are 0 homozygotes in gnomad4_exome. There are 307 alleles in male gnomad4_exome subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 28 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARID1B	NM_001374828.1	c.370_372del	p.Ser124del	inframe_deletion	1/20	ENST00000636930.2
LOC115308161	NR_163974.1	n.273+212_273+214del		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARID1B	ENST00000636930.2	c.370_372del	p.Ser124del	inframe_deletion	1/20	2	NM_001374828.1	A2
	ENST00000603191.2	n.177+212_177+214del		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.000187 AC: 28 AN: 150034 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000146

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000132

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000209

Gnomad FIN AF: 0.000292

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000224

Gnomad OTH AF: 0.000485

GnomAD3 exomes AF: 0.00289 AC: 307 AN: 106066 Hom.: 0 AF XY: 0.00276 AC XY: 159 AN XY: 57628

Gnomad AFR exome AF: 0.00325

Gnomad AMR exome AF: 0.00261

Gnomad ASJ exome AF: 0.00315

Gnomad EAS exome AF: 0.00177

Gnomad SAS exome AF: 0.00252

Gnomad FIN exome AF: 0.00623

Gnomad NFE exome AF: 0.00292

Gnomad OTH exome AF: 0.00303

GnomAD4 exome AF: 0.000428 AC: 570 AN: 1332780 Hom.: 0 AF XY: 0.000468 AC XY: 307 AN XY: 655944

Gnomad4 AFR exome AF: 0.000770

Gnomad4 AMR exome AF: 0.00154

Gnomad4 ASJ exome AF: 0.000967

Gnomad4 EAS exome AF: 0.000676

Gnomad4 SAS exome AF: 0.000760

Gnomad4 FIN exome AF: 0.00181

Gnomad4 NFE exome AF: 0.000283

Gnomad4 OTH exome AF: 0.000558

GnomAD4 genome AF: 0.000186 AC: 28 AN: 150140 Hom.: 0 Cov.: 30 AF XY: 0.000150 AC XY: 11 AN XY: 73328

Gnomad4 AFR AF: 0.000146

Gnomad4 AMR AF: 0.000132

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000209

Gnomad4 FIN AF: 0.000292

Gnomad4 NFE AF: 0.000224

Gnomad4 OTH AF: 0.000480

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 30, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 08, 2019	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jul 03, 2014

- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 13, 2016

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

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 20, 2020

This variant is classified as 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

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

LitVar

Other links and lift over

dbSNP: rs770512547; hg19: chr6-157099165;