rs1429977258

Variant names:

• chr1-26696596-C-G
• rs1429977258
• NM_006015.6:c.193C>G

Your query was ambiguous. Multiple possible variants found:

• chr1-26696596-C-G
• chr1-26696596-C-T

Variant summary

Our verdict is Likely benign. The variant received -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. 14/22 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:2 B:1
• Conservation: PhyloP100: 1.14
• Publications: 4 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)

LOC124900417 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -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 VariationId is 445779.

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.193C>G	p.Pro65Ala	missense	Exon 1 of 20	NP_006006.3
	ARID1A	NM_139135.4		c.193C>G	p.Pro65Ala	missense	Exon 1 of 20	NP_624361.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARID1A	ENST00000324856.13	TSL:1 MANE Select	c.193C>G	p.Pro65Ala	missense	Exon 1 of 20	ENSP00000320485.7
	ARID1A	ENST00000850904.1		c.193C>G	p.Pro65Ala	missense	Exon 1 of 20	ENSP00000520984.1
	ARID1A	ENST00000457599.7	TSL:5	c.193C>G	p.Pro65Ala	missense	Exon 1 of 20	ENSP00000387636.2

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

African (AFR) AF: 0.00 AC: 0 AN: 22612

American (AMR) AF: 0.00 AC: 0 AN: 8146

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14056

East Asian (EAS) AF: 0.00 AC: 0 AN: 25986

South Asian (SAS) AF: 0.00 AC: 0 AN: 21020

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 21756

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2894

European-Non Finnish (NFE) AF: 0.00000217 AC: 2 AN: 922336

Other (OTH) AF: 0.00 AC: 0 AN: 43356

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

African (AFR) AF: 0.00 AC: 0 AN: 41076

American (AMR) AF: 0.00 AC: 0 AN: 15186

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3456

East Asian (EAS) AF: 0.00 AC: 0 AN: 5044

South Asian (SAS) AF: 0.00 AC: 0 AN: 4802

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10338

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 308

European-Non Finnish (NFE) AF: 0.0000296 AC: 2 AN: 67570

Other (OTH) AF: 0.00 AC: 0 AN: 2072

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Pathogenic	0.84	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	0.0	N
PhyloP100		1.1
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	0.39	N
REVEL	Benign	0.043
Sift	Pathogenic	0.0	D
Sift4G	Benign	1.0	T
Polyphen		0.0040	B
Vest4		0.27
MVP		0.16
MPC		0.50
ClinPred		0.29	T
GERP RS		2.2
PromoterAI		-0.068	Neutral
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		3.9
Varity_R		0.13
gMVP		0.091
Mutation Taster		=83/17	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: rs1429977258; hg19: chr1-27023087;