1-26696407-G-T

Variant names:

• chr1-26696407-G-T
• rs1333869920
• NM_006015.6:c.4G>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_006015.6(ARID1A):​c.4G>T​(p.Ala2Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000706 in 1,133,926 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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. A2T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000071 (0 hom.)
• Consequence: ARID1A NM_006015.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.50
• Publications: 3 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: ClinGen, Orphanet
• intellectual disability, autosomal dominant 14

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

LOC124900417 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.41759947).
• BS2: High AC in GnomAdExome4 at 8 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006015.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARID1A	NM_006015.6	MANE Select	c.4G>T	p.Ala2Ser	missense	Exon 1 of 20	NP_006006.3
	ARID1A	NM_139135.4		c.4G>T	p.Ala2Ser	missense	Exon 1 of 20	NP_624361.1	O14497-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARID1A	ENST00000324856.13	TSL:1 MANE Select	c.4G>T	p.Ala2Ser	missense	Exon 1 of 20	ENSP00000320485.7	O14497-1
	ARID1A	ENST00000850904.1		c.4G>T	p.Ala2Ser	missense	Exon 1 of 20	ENSP00000520984.1	A0ABJ7H312
	ARID1A	ENST00000457599.7	TSL:5	c.4G>T	p.Ala2Ser	missense	Exon 1 of 20	ENSP00000387636.2	O14497-2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000706 AC: 8 AN: 1133926 Hom.: 0 Cov.: 35 AF XY: 0.00000727 AC XY: 4 AN XY: 549984

African (AFR) AF: 0.00 AC: 0 AN: 22886

American (AMR) AF: 0.00 AC: 0 AN: 10238

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15142

East Asian (EAS) AF: 0.00 AC: 0 AN: 25794

South Asian (SAS) AF: 0.00 AC: 0 AN: 37558

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 23676

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3014

European-Non Finnish (NFE) AF: 0.00000631 AC: 6 AN: 950692

Other (OTH) AF: 0.0000445 AC: 2 AN: 44926

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Benign	-0.069	T
BayesDel_noAF	Benign	-0.34
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Benign	0.46	N
LIST_S2	Benign	0.54	T
M_CAP	Pathogenic	0.72	D
MetaRNN	Benign	0.42	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.97	L
PhyloP100		2.5
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-0.67	N
REVEL	Benign	0.051
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.81	T
Polyphen		0.85	P
Vest4		0.26
MutPred		0.15		Gain of loop (P = 0.0097)
MVP		0.30
MPC		0.61
ClinPred		0.49	T
GERP RS		3.9
PromoterAI		-0.31	Neutral
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		3.0
Varity_R		0.42
gMVP		0.53
Mutation Taster		=79/21	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs1333869920; hg19: chr1-27022898;