rs1553145891

chr1-26696642-A-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_006015.6(ARID1A):c.239A>G(p.Asn80Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,297,950 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0000067 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000061 (0 hom.)
• Consequence: ARID1A NM_006015.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.276

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 Likely_benign. Variant got -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.096542895).
• BP6: Variant 1-26696642-A-G is Benign according to our data. Variant chr1-26696642-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 434348.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARID1A	NM_006015.6	c.239A>G	p.Asn80Ser	missense_variant	1/20	ENST00000324856.13
ARID1A	NM_139135.4	c.239A>G	p.Asn80Ser	missense_variant	1/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARID1A	ENST00000324856.13	c.239A>G	p.Asn80Ser	missense_variant	1/20	1	NM_006015.6
ARID1A	ENST00000457599.6	c.239A>G	p.Asn80Ser	missense_variant	1/20	5
ARID1A	ENST00000430799.7	c.-13+3025A>G		intron_variant		5		A2
ARID1A	ENST00000637465.1	c.-13+542A>G		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.00000673 AC: 1 AN: 148600 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000224

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000609 AC: 7 AN: 1149350 Hom.: 0 Cov.: 35 AF XY: 0.00000898 AC XY: 5 AN XY: 556948

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000160

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000104

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000673 AC: 1 AN: 148600 Hom.: 0 Cov.: 32 AF XY: 0.0000138 AC XY: 1 AN XY: 72478

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000224

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 07, 2020	Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Benign, criteria provided, single submitter	clinical testing	Invitae	Oct 24, 2023	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

May 26, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
Cadd	Benign	21
Dann	Benign	0.83
DEOGEN2	Benign	0.081	T;.
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.81	T;T
M_CAP	Pathogenic	0.60	D
MetaRNN	Benign	0.097	T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.0	N;N
MutationTaster	Benign	0.98	N;N
PrimateAI	Pathogenic	0.96	D
PROVEAN	Benign	0.040	N;N
REVEL	Benign	0.043
Sift	Benign	0.071	T;T
Sift4G	Benign	0.75	T;T
Polyphen		0.0020	B;B
Vest4		0.37
MutPred		0.17		Gain of glycosylation at N80 (P = 9e-04);Gain of glycosylation at N80 (P = 9e-04);
MVP		0.27
MPC		0.41
ClinPred		0.11	T
GERP RS		3.2
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		3.0
Varity_R		0.12
gMVP		0.11

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: rs1553145891; hg19: chr1-27023133; COSMIC: COSV99081673; COSMIC: COSV99081673;