1-26696875-C-T

Variant names:

• chr1-26696875-C-T
• rs567246585
• NM_006015.6:c.472C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006015.6(ARID1A):​c.472C>T​(p.Pro158Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00137 in 1,360,252 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P158L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00086 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (1 hom.)
• Consequence: ARID1A NM_006015.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 2.11
• Publications: 5 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0060768723).
• BP6: Variant 1-26696875-C-T is Benign according to our data. Variant chr1-26696875-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 376870.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00086 (130/151162) while in subpopulation NFE AF = 0.00161 (109/67650). AF 95% confidence interval is 0.00137. There are 0 homozygotes in GnomAd4. There are 51 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 130 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.472C>T	p.Pro158Ser	missense	Exon 1 of 20	NP_006006.3
	ARID1A	NM_139135.4		c.472C>T	p.Pro158Ser	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.472C>T	p.Pro158Ser	missense	Exon 1 of 20	ENSP00000320485.7	O14497-1
	ARID1A	ENST00000850904.1		c.472C>T	p.Pro158Ser	missense	Exon 1 of 20	ENSP00000520984.1	A0ABJ7H312
	ARID1A	ENST00000457599.7	TSL:5	c.472C>T	p.Pro158Ser	missense	Exon 1 of 20	ENSP00000387636.2	O14497-2

Frequencies

GnomAD3 genomes AF: 0.000867 AC: 131 AN: 151050 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000219

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000526

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000837

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00161

Gnomad OTH AF: 0.000482

GnomAD2 exomes AF: 0.000699 AC: 13 AN: 18610 AF XY: 0.000295

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000248

Gnomad NFE exome AF: 0.00136

Gnomad OTH exome AF: 0.00376

GnomAD4 exome AF: 0.00143 AC: 1733 AN: 1209090 Hom.: 1 Cov.: 35 AF XY: 0.00137 AC XY: 803 AN XY: 585942

African (AFR) AF: 0.000291 AC: 7 AN: 24022

American (AMR) AF: 0.000425 AC: 4 AN: 9402

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16416

East Asian (EAS) AF: 0.00 AC: 0 AN: 27796

South Asian (SAS) AF: 0.000210 AC: 10 AN: 47520

European-Finnish (FIN) AF: 0.000276 AC: 11 AN: 39878

Middle Eastern (MID) AF: 0.000422 AC: 2 AN: 4742

European-Non Finnish (NFE) AF: 0.00167 AC: 1651 AN: 990244

Other (OTH) AF: 0.000978 AC: 48 AN: 49070

GnomAD4 genome AF: 0.000860 AC: 130 AN: 151162 Hom.: 0 Cov.: 32 AF XY: 0.000691 AC XY: 51 AN XY: 73830

African (AFR) AF: 0.000218 AC: 9 AN: 41232

American (AMR) AF: 0.000526 AC: 8 AN: 15220

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3454

East Asian (EAS) AF: 0.00 AC: 0 AN: 5048

South Asian (SAS) AF: 0.000628 AC: 3 AN: 4776

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10496

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 282

European-Non Finnish (NFE) AF: 0.00161 AC: 109 AN: 67650

Other (OTH) AF: 0.000477 AC: 1 AN: 2096

Alfa AF: 0.00101 Hom.: 0

Bravo AF: 0.000797

ExAC AF: 0.000473 AC: 45

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	Coffin-Siris syndrome (1)
-	-	1	Intellectual disability, autosomal dominant 14 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.58
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.70	T
M_CAP	Pathogenic	0.36	D
MetaRNN	Benign	0.0061	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.97	L
PhyloP100		2.1
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-0.80	N
REVEL	Benign	0.074
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.53	T
Polyphen		0.0	B
Vest4		0.17
MVP		0.22
MPC		0.52
ClinPred		0.21	T
GERP RS		2.0
PromoterAI		0.037	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.27
gMVP		0.34
Mutation Taster		=63/37	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: rs567246585; hg19: chr1-27023366;