rs1429977258

chr1-26696596-C-Gchr1-26696596-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_006015.6(ARID1A):c.193C>G(p.Pro65Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000324 in 1,232,920 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P65L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000018 (0 hom.)
• Consequence: ARID1A NM_006015.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 1.14

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 -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15775216).
• BP6: Variant 1-26696596-C-G is Benign according to our data. Variant chr1-26696596-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 445779.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARID1A	NM_006015.6	c.193C>G	p.Pro65Ala	missense_variant	1/20	ENST00000324856.13
ARID1A	NM_139135.4	c.193C>G	p.Pro65Ala	missense_variant	1/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARID1A	ENST00000324856.13	c.193C>G	p.Pro65Ala	missense_variant	1/20	1	NM_006015.6
ARID1A	ENST00000457599.6	c.193C>G	p.Pro65Ala	missense_variant	1/20	5
ARID1A	ENST00000430799.7	c.-13+2979C>G		intron_variant		5		A2
ARID1A	ENST00000637465.1	c.-13+496C>G		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.0000133 AC: 2 AN: 150758 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: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000296

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000185 AC: 2 AN: 1082162 Hom.: 0 Cov.: 35 AF XY: 0.00000390 AC XY: 2 AN XY: 512888

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000217

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000133 AC: 2 AN: 150758 Hom.: 0 Cov.: 32 AF XY: 0.0000136 AC XY: 1 AN XY: 73612

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000296

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 15, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 07, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	23
Dann	Benign	0.91
DEOGEN2	Benign	0.073	T;.
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.078	N
LIST_S2	Benign	0.63	T;T
M_CAP	Pathogenic	0.84	D
MetaRNN	Benign	0.16	T;T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	0.0	N;N
MutationTaster	Benign	0.72	D;D
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	0.39	N;N
REVEL	Benign	0.043
Sift	Pathogenic	0.0	D;D
Sift4G	Benign	1.0	T;T
Polyphen		0.0040	B;B
Vest4		0.27
MVP		0.16
MPC		0.50
ClinPred		0.29	T
GERP RS		2.2
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		3.9
Varity_R		0.13
gMVP		0.091

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: rs1429977258; hg19: chr1-27023087;