rs41303631

chr1-26779615-G-Achr1-26779615-G-Cchr1-26779615-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_006015.6(ARID1A):c.5717G>A(p.Arg1906Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00218 in 1,614,074 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 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. R1906P) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (7 hom.)
• Consequence: ARID1A NM_006015.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9 O:1
• Conservation: PhyloP100: 2.36

Genes affected

ARID1A (HGNC:11110): (AT-rich interaction domain 1A) This gene encodes a member of the SWI/SNF family, whose members have helicase and ATPase activities and are thought to regulate transcription of certain genes by altering the chromatin structure around those genes. The encoded protein is part of the large ATP-dependent chromatin remodeling complex SNF/SWI, which is required for transcriptional activation of genes normally repressed by chromatin. It possesses at least two conserved domains that could be important for its function. First, it has a DNA-binding domain that can specifically bind an AT-rich DNA sequence known to be recognized by a SNF/SWI complex at the beta-globin locus. Second, the C-terminus of the protein can stimulate glucocorticoid receptor-dependent transcriptional activation. It is thought that the protein encoded by this gene confers specificity to the SNF/SWI complex and may recruit the complex to its targets through either protein-DNA or protein-protein interactions. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010280728).
• BP6: Variant 1-26779615-G-A is Benign according to our data. Variant chr1-26779615-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 133552.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-26779615-G-A is described in Lovd as [Benign]. Variant chr1-26779615-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00152 (231/152186) while in subpopulation NFE AF= 0.00257 (175/68010). AF 95% confidence interval is 0.00226. There are 0 homozygotes in gnomad4. There are 104 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 231 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARID1A	NM_006015.6	c.5717G>A	p.Arg1906Gln	missense_variant	20/20	ENST00000324856.13
ARID1A	NM_139135.4	c.5066G>A	p.Arg1689Gln	missense_variant	20/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARID1A	ENST00000324856.13	c.5717G>A	p.Arg1906Gln	missense_variant	20/20	1	NM_006015.6

Frequencies

GnomAD3 genomes AF: 0.00152 AC: 231 AN: 152068 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000749

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00132

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00257

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00153 AC: 384 AN: 251396 Hom.: 1 AF XY: 0.00159 AC XY: 216 AN XY: 135890

Gnomad AFR exome AF: 0.000616

Gnomad AMR exome AF: 0.000694

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000261

Gnomad FIN exome AF: 0.00162

Gnomad NFE exome AF: 0.00264

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00225 AC: 3294 AN: 1461888 Hom.: 7 Cov.: 31 AF XY: 0.00222 AC XY: 1614 AN XY: 727242

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.000604

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000267

Gnomad4 FIN exome AF: 0.00159

Gnomad4 NFE exome AF: 0.00273

Gnomad4 OTH exome AF: 0.00176

GnomAD4 genome AF: 0.00152 AC: 231 AN: 152186 Hom.: 0 Cov.: 32 AF XY: 0.00140 AC XY: 104 AN XY: 74418

Gnomad4 AFR AF: 0.000747

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00132

Gnomad4 NFE AF: 0.00257

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00210 Hom.: 2

Bravo AF: 0.00143

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00302 AC: 26

ExAC AF: 0.00157 AC: 191

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00284

EpiControl AF: 0.00225

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	ARID1A: BP4, BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 12, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 17, 2020	This variant is associated with the following publications: (PMID: 24728327, 28767289) -

not specified Benign:2 Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 26, 2016	- -

ARID1A-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 07, 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). -

Intellectual disability, autosomal dominant 14 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.41
Cadd	Uncertain	24
Dann	Uncertain	1.0
Eigen	Benign	0.14
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.97	D;D;D;D;D
M_CAP	Benign	0.0068	T
MetaRNN	Benign	0.010	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.62	D;D;D;N
PrimateAI	Uncertain	0.56	T
Polyphen		0.72, 1.0, 0.67	.;P;D;P;.
Vest4		0.15, 0.34, 0.18
MVP		0.50
MPC		0.61
ClinPred		0.012	T
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.14
gMVP		0.33

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: rs41303631; hg19: chr1-27106106; COSMIC: COSV61377691; COSMIC: COSV61377691;