Genetic Variant ARID1A:p.Ala45Ala (chr1-26696538-C-T) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_006015.6(ARID1A):c.135C>T(p.Ala45Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000322 in 1,223,954 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A45A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0016 ( 2 hom., cov: 32)

Exomes 𝑓: 0.00015 ( 2 hom. )

Consequence

ARID1A
NM_006015.6 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 1.23

Publications

0 publications found

Variant links:

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

ARID1A links:

LOC124900417 (HGNC:):

LOC124900417 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.41).

BP6

Variant 1-26696538-C-T is Benign according to our data. Variant chr1-26696538-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 434311.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.23 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00159 (233/146468) while in subpopulation AFR AF = 0.00566 (225/39772). AF 95% confidence interval is 0.00505. There are 2 homozygotes in GnomAd4. There are 95 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 233 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.135C>T	p.Ala45Ala	synonymous	Exon 1 of 20	NP_006006.3
	ARID1A	NM_139135.4		c.135C>T	p.Ala45Ala	synonymous	Exon 1 of 20	NP_624361.1	O14497-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ARID1A	ENST00000324856.13	TSL:1 MANE Select	c.135C>T	p.Ala45Ala	synonymous	Exon 1 of 20	ENSP00000320485.7	O14497-1
ARID1A	ENST00000850904.1		c.135C>T	p.Ala45Ala	synonymous	Exon 1 of 20	ENSP00000520984.1	A0ABJ7H312
ARID1A	ENST00000457599.7	TSL:5	c.135C>T	p.Ala45Ala	synonymous	Exon 1 of 20	ENSP00000387636.2	O14497-2

Frequencies

GnomAD3 genomes

AF:

0.00159

AC:

232

AN:

146356

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00565

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000402

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:

0.0000304

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00

AC:

AN:

308

AF XY:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000149

AC:

161

AN:

1077486

Hom.:

Cov.:

AF XY:

0.000139

AC XY:

AN XY:

511436

show subpopulations

African (AFR)

AF:

0.00673

AC:

151

AN:

22422

American (AMR)

AF:

0.000375

AC:

AN:

8004

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

13688

East Asian (EAS)

AF:

0.00

AC:

AN:

25546

South Asian (SAS)

AF:

0.00

AC:

AN:

20478

European-Finnish (FIN)

AF:

0.00

AC:

AN:

21168

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2868

European-Non Finnish (NFE)

AF:

0.00000217

AC:

AN:

920332

Other (OTH)

AF:

0.000116

AC:

AN:

42980

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00159

AC:

233

AN:

146468

Hom.:

Cov.:

AF XY:

0.00133

AC XY:

AN XY:

71602

show subpopulations

African (AFR)

AF:

0.00566

AC:

225

AN:

39772

American (AMR)

AF:

0.000402

AC:

AN:

14942

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3416

East Asian (EAS)

AF:

0.00

AC:

AN:

4840

South Asian (SAS)

AF:

0.00

AC:

AN:

4626

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9856

Middle Eastern (MID)

AF:

0.00

AC:

AN:

262

European-Non Finnish (NFE)

AF:

0.0000304

AC:

AN:

65866

Other (OTH)

AF:

0.00

AC:

AN:

2030

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00121

Hom.:

Bravo

AF:

0.00163

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Intellectual disability, autosomal dominant 14 (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.41

CADD

Benign

(source)

DANN

Uncertain

0.98

PhyloP100

1.2

PromoterAI

-0.018

Neutral

(source)

RBP_binding_hub_radar

1.1

RBP_regulation_power_radar

2.3

Mutation Taster

=100/0

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over