NM_006015.6:c.326C>T

Variant names:

• chr1-26696729-C-T
• rs1167372383
• NM_006015.6:c.326C>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.326C>T​(p.Pro109Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000218 in 1,376,144 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. P109S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000016 (0 hom.)
• Consequence: ARID1A NM_006015.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.223
• Publications: 2 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

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=0.23374397).
• BP6: Variant 1-26696729-C-T is Benign according to our data. Variant chr1-26696729-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 434331.

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.326C>T	p.Pro109Leu	missense	Exon 1 of 20	NP_006006.3
	ARID1A	NM_139135.4		c.326C>T	p.Pro109Leu	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.326C>T	p.Pro109Leu	missense	Exon 1 of 20	ENSP00000320485.7	O14497-1
	ARID1A	ENST00000850904.1		c.326C>T	p.Pro109Leu	missense	Exon 1 of 20	ENSP00000520984.1	A0ABJ7H312
	ARID1A	ENST00000457599.7	TSL:5	c.326C>T	p.Pro109Leu	missense	Exon 1 of 20	ENSP00000387636.2	O14497-2

Frequencies

GnomAD3 genomes AF: 0.00000665 AC: 1 AN: 150320 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: 0.000200

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000163 AC: 2 AN: 1225712 Hom.: 0 Cov.: 35 AF XY: 0.00000333 AC XY: 2 AN XY: 600310

African (AFR) AF: 0.00 AC: 0 AN: 24078

American (AMR) AF: 0.00 AC: 0 AN: 12450

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18344

East Asian (EAS) AF: 0.00 AC: 0 AN: 27426

South Asian (SAS) AF: 0.0000183 AC: 1 AN: 54636

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36852

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3694

European-Non Finnish (NFE) AF: 0.00000100 AC: 1 AN: 998570

Other (OTH) AF: 0.00 AC: 0 AN: 49662

GnomAD4 genome AF: 0.00000665 AC: 1 AN: 150432 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 73536

African (AFR) AF: 0.00 AC: 0 AN: 40982

American (AMR) AF: 0.00 AC: 0 AN: 15198

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3450

East Asian (EAS) AF: 0.000201 AC: 1 AN: 4982

South Asian (SAS) AF: 0.00 AC: 0 AN: 4786

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10368

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 278

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67396

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.56
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T
Eigen	Benign	0.093
Eigen_PC	Benign	0.081
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.75	T
M_CAP	Pathogenic	0.80	D
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.22
PrimateAI	Pathogenic	0.97	D
PROVEAN	Benign	-0.64	N
REVEL	Benign	0.061
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.22	T
Polyphen		0.95	P
Vest4		0.27
MutPred		0.28		Loss of methylation at R110 (P = 0.1218)
MVP		0.33
MPC		0.53
ClinPred		0.26	T
GERP RS		2.8
PromoterAI		0.060	Neutral
Varity_R		0.25
gMVP		0.24
Mutation Taster		=60/40	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: rs1167372383; hg19: chr1-27023220; COSMIC: COSV61392260;