1-26779126-C-G

Variant names:

• chr1-26779126-C-G
• rs528936858
• NM_006015.6:c.5228C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_006015.6(ARID1A):​c.5228C>G​(p.Thr1743Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1743M) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ARID1A NM_006015.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.43
• Publications: 0 publications found

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]

ARID1A Gene-Disease associations (from GenCC):

• Coffin-Siris syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• intellectual disability, autosomal dominant 14

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Illumina, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARID1A	NM_006015.6	c.5228C>G	p.Thr1743Arg	missense_variant	Exon 20 of 20	ENST00000324856.13	NP_006006.3
ARID1A	NM_139135.4	c.4577C>G	p.Thr1526Arg	missense_variant	Exon 20 of 20		NP_624361.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARID1A	ENST00000324856.13	c.5228C>G	p.Thr1743Arg	missense_variant	Exon 20 of 20	1	NM_006015.6	ENSP00000320485.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.26	.;T;.;.;T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.96	D;D;D;D;D
M_CAP	Benign	0.015	T
MetaRNN	Uncertain	0.50	D;D;D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	.;M;.;.;.
PhyloP100		7.4
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-2.5	.;D;N;D;.
REVEL	Benign	0.29
Sift	Uncertain	0.025	.;D;T;D;.
Sift4G	Uncertain	0.0070	.;D;T;D;.
Polyphen		0.88, 1.0, 0.93	.;P;D;P;.
Vest4		0.76, 0.86, 0.70
MutPred		0.20		.;Loss of loop (P = 0.0235);.;.;.;
MVP		0.53
MPC		1.2
ClinPred		0.97	D
GERP RS		5.0
Varity_R		0.55
gMVP		0.70
Mutation Taster		=63/37	polymorphism

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

Other links and lift over

dbSNP: rs528936858; hg19: chr1-27105617;