rs140946580

chr1-26779234-A-G

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.5336A>G(p.Glu1779Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0014 in 1,614,112 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (3 hom.)
• Consequence: ARID1A NM_006015.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: 3.00

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=0.0045731068).
• BP6: Variant 1-26779234-A-G is Benign according to our data. Variant chr1-26779234-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 133551.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00102 (156/152332) while in subpopulation NFE AF= 0.00128 (87/68030). AF 95% confidence interval is 0.00106. There are 0 homozygotes in gnomad4. There are 94 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 156 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARID1A	NM_006015.6	c.5336A>G	p.Glu1779Gly	missense_variant	20/20	ENST00000324856.13
ARID1A	NM_139135.4	c.4685A>G	p.Glu1562Gly	missense_variant	20/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARID1A	ENST00000324856.13	c.5336A>G	p.Glu1779Gly	missense_variant	20/20	1	NM_006015.6

Frequencies

GnomAD3 genomes AF: 0.00102 AC: 156 AN: 152214 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00547

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00128

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00116 AC: 291 AN: 251322 Hom.: 0 AF XY: 0.00121 AC XY: 165 AN XY: 135828

Gnomad AFR exome AF: 0.000370

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.00527

Gnomad NFE exome AF: 0.00141

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.00144 AC: 2102 AN: 1461780 Hom.: 3 Cov.: 31 AF XY: 0.00141 AC XY: 1028 AN XY: 727172

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000232

Gnomad4 FIN exome AF: 0.00475

Gnomad4 NFE exome AF: 0.00159

Gnomad4 OTH exome AF: 0.000944

GnomAD4 genome AF: 0.00102 AC: 156 AN: 152332 Hom.: 0 Cov.: 32 AF XY: 0.00126 AC XY: 94 AN XY: 74470

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00547

Gnomad4 NFE AF: 0.00128

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00124 Hom.: 0

Bravo AF: 0.000684

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.00126 AC: 153

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00104

EpiControl AF: 0.00130

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 11, 2020	This variant is associated with the following publications: (PMID: 29273094, 24382590, 28767289) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	ARID1A: BP4, BS1 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 19, 2023	- -

not specified Benign:1 Other:1

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 29, 2017	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -

ARID1A-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 26, 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	0.078
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.44
Cadd	Uncertain	23
Dann	Uncertain	0.99
Eigen	Benign	0.066
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.40	T;T;T;T;T
M_CAP	Benign	0.0047	T
MetaRNN	Benign	0.0046	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.69	D;D;N;N
PrimateAI	Benign	0.47	T
Polyphen		0.48, 0.62, 0.073	.;P;P;B;.
Vest4		0.28, 0.35, 0.22
MVP		0.33
MPC		0.61
ClinPred		0.041	T
GERP RS		5.1
Varity_R		0.14
gMVP		0.25

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: rs140946580; hg19: chr1-27105725; COSMIC: COSV61373637; COSMIC: COSV61373637;