6-157198907-G-A

Variant names:

• chr6-157198907-G-A
• rs797045277
• NM_001374828.1:c.4479G>A

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PS3 PM2 PP3_Strong PP5_Very_Strong

The NM_001374828.1(ARID1B):​c.4479G>A​(p.Pro1493Pro) variant causes a splice region, synonymous change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV005397712: This variant causes exon 17 to be skipped, resulting in a frameshift and early termination (p.Arg1338ArgfsTer76) (PMID:27474218)." and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. P1493P) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ARID1B NM_001374828.1 splice_region, synonymous
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:16 U:1
• Conservation: PhyloP100: 9.43
• Publications: 5 publications found

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)

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV005397712: This variant causes exon 17 to be skipped, resulting in a frameshift and early termination (p.Arg1338ArgfsTer76) (PMID: 27474218).; SCV007096586: A minigene splicing assay has shown that this variant results in the skipping of exon 17 and subsequently introduces a premature termination codon 76 amino acids downstream (PMID: 22405089); SCV003439486: RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product.; SCV001445039: RNA functional analysis demonstrated that the alteration leads to out-of-frame skipping of exon 17 (Hoyer, 2012).; SCV004107837: cDNA analyses indicated that this variant causes skipping of exon 17 and a shift to the translation reading frame (p.Arg1338Argfs*76, Hoyer et al. 2012. PubMed ID: 22405089)
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• PP5: Variant 6-157198907-G-A is Pathogenic according to our data. Variant chr6-157198907-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 210291.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARID1B	NM_001374828.1	MANE Select	c.4479G>A	p.Pro1493Pro	splice_region synonymous	Exon 17 of 20	NP_001361757.1	A0A6Q8NVI4
	ARID1B	NM_001438482.1		c.4608G>A	p.Pro1536Pro	splice_region synonymous	Exon 18 of 21	NP_001425411.1
	ARID1B	NM_001438483.1		c.4521G>A	p.Pro1507Pro	splice_region synonymous	Exon 18 of 21	NP_001425412.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARID1B	ENST00000636930.2	TSL:2 MANE Select	c.4479G>A	p.Pro1493Pro	splice_region synonymous	Exon 17 of 20	ENSP00000490491.2	A0A6Q8NVI4
	ARID1B	ENST00000346085.10	TSL:1	c.4359G>A	p.Pro1453Pro	splice_region synonymous	Exon 18 of 21	ENSP00000344546.5	A0A3F2YNW7
	ARID1B	ENST00000350026.11	TSL:1	c.4320G>A	p.Pro1440Pro	splice_region synonymous	Exon 16 of 19	ENSP00000055163.8	Q8NFD5-5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1445994 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 717232

African (AFR) AF: 0.00 AC: 0 AN: 33314

American (AMR) AF: 0.00 AC: 0 AN: 43326

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25788

East Asian (EAS) AF: 0.00 AC: 0 AN: 39294

South Asian (SAS) AF: 0.00 AC: 0 AN: 83956

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52494

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5480

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1102738

Other (OTH) AF: 0.00 AC: 0 AN: 59604

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000645 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
9	-	-	Coffin-Siris syndrome 1 (9)
2	-	-	not provided (2)
2	-	-	See cases (2)
1	-	-	ARID1B-related BAFopathy (1)
1	-	-	ARID1B-related disorder (1)
-	1	-	Constipation;C0036572:Seizure;C0349588:Short stature;C2315100:Failure to thrive;C3806482:Recurrent respiratory infections;C4551563:Microcephaly;C5574742:Decreased body weight (1)
1	-	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.19
CADD	Benign	23
DANN	Benign	0.94
PhyloP100		9.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Mutation Taster		=14/86	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs797045277; hg19: chr6-157520041;