NM_006015.6:c.358C>T

Variant names:

• chr1-26696761-C-T
• rs571264557
• NM_006015.6:c.358C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_006015.6(ARID1A):​c.358C>T​(p.Pro120Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000915 in 1,352,836 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 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. P120L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0052 (10 hom., cov: 32)
  • Exomes 𝑓: 0.00038 (6 hom.)
• Consequence: ARID1A NM_006015.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 1.44
• Publications: 6 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0033951402).
• BP6: Variant 1-26696761-C-T is Benign according to our data. Variant chr1-26696761-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 434332.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00515 (777/150768) while in subpopulation AFR AF = 0.0181 (745/41124). AF 95% confidence interval is 0.017. There are 10 homozygotes in GnomAd4. There are 384 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 777 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.358C>T	p.Pro120Ser	missense	Exon 1 of 20	NP_006006.3
	ARID1A	NM_139135.4		c.358C>T	p.Pro120Ser	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.358C>T	p.Pro120Ser	missense	Exon 1 of 20	ENSP00000320485.7	O14497-1
	ARID1A	ENST00000850904.1		c.358C>T	p.Pro120Ser	missense	Exon 1 of 20	ENSP00000520984.1	A0ABJ7H312
	ARID1A	ENST00000457599.7	TSL:5	c.358C>T	p.Pro120Ser	missense	Exon 1 of 20	ENSP00000387636.2	O14497-2

Frequencies

GnomAD3 genomes AF: 0.00516 AC: 778 AN: 150658 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.0182

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00178

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: 0.00

Gnomad OTH AF: 0.00242

GnomAD2 exomes AF: 0.000271 AC: 4 AN: 14766 AF XY: 0.000222

Gnomad AFR exome AF: 0.0273

Gnomad AMR exome AF: 0.00144

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000384 AC: 461 AN: 1202068 Hom.: 6 Cov.: 35 AF XY: 0.000317 AC XY: 185 AN XY: 584438

African (AFR) AF: 0.0167 AC: 394 AN: 23610

American (AMR) AF: 0.00176 AC: 17 AN: 9658

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17082

East Asian (EAS) AF: 0.00 AC: 0 AN: 27238

South Asian (SAS) AF: 0.00 AC: 0 AN: 47428

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35706

Middle Eastern (MID) AF: 0.000271 AC: 1 AN: 3686

European-Non Finnish (NFE) AF: 0.0000111 AC: 11 AN: 988874

Other (OTH) AF: 0.000779 AC: 38 AN: 48786

GnomAD4 genome AF: 0.00515 AC: 777 AN: 150768 Hom.: 10 Cov.: 32 AF XY: 0.00521 AC XY: 384 AN XY: 73692

African (AFR) AF: 0.0181 AC: 745 AN: 41124

American (AMR) AF: 0.00178 AC: 27 AN: 15194

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4790

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10380

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67492

Other (OTH) AF: 0.00239 AC: 5 AN: 2092

Alfa AF: 0.00885 Hom.: 3

Bravo AF: 0.00595

ExAC AF: 0.000111 AC: 2

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	ARID1A-related disorder (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	23
DANN	Benign	0.97
DEOGEN2	Benign	0.053	T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.63	T
MetaRNN	Benign	0.0034	T
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	0.0	N
PhyloP100		1.4
PrimateAI	Pathogenic	0.96	D
PROVEAN	Benign	0.57	N
REVEL	Benign	0.077
Sift	Benign	0.082	T
Sift4G	Benign	0.87	T
Polyphen		0.44	B
Vest4		0.18
MutPred		0.18		Loss of catalytic residue at P120 (P = 0.0094)
MVP		0.27
MPC		0.52
ClinPred		0.026	T
GERP RS		3.6
PromoterAI		0.00080	Neutral
Varity_R		0.099
gMVP		0.098
Mutation Taster		=96/4	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: rs571264557; hg19: chr1-27023252; COSMIC: COSV61373973; COSMIC: COSV61373973;