rs571264557

Positions:

• chr1-26696761-C-T

Variant summary

Our verdict is Benign. Variant got -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. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P120L) has been classified as 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

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 434332.We mark this variant Likely_benign, oryginal submissions are: {Benign=4, Uncertain_significance=1}.
• 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 777 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARID1A	NM_006015.6	c.358C>T	p.Pro120Ser	missense_variant	1/20	ENST00000324856.13
ARID1A	NM_139135.4	c.358C>T	p.Pro120Ser	missense_variant	1/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARID1A	ENST00000324856.13	c.358C>T	p.Pro120Ser	missense_variant	1/20	1	NM_006015.6
ARID1A	ENST00000457599.6	c.358C>T	p.Pro120Ser	missense_variant	1/20	5
ARID1A	ENST00000430799.7	c.-13+3144C>T		intron_variant		5		A2
ARID1A	ENST00000637465.1	c.-13+661C>T		intron_variant		5

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

GnomAD3 exomes AF: 0.000271 AC: 4 AN: 14766 Hom.: 0 AF XY: 0.000222 AC XY: 2 AN XY: 9012

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 SAS 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

Gnomad4 AFR exome AF: 0.0167

Gnomad4 AMR exome AF: 0.00176

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000111

Gnomad4 OTH exome AF: 0.000779

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

Gnomad4 AFR AF: 0.0181

Gnomad4 AMR AF: 0.00178

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00239

Alfa AF: 0.00451 Hom.: 0

Bravo AF: 0.00595

ExAC AF: 0.000111 AC: 2

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2023	ARID1A: PP2, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 23, 2020	This variant is associated with the following publications: (PMID: 23906836) -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

May 26, 2016

- -

ARID1A-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 26, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

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;T
MetaRNN	Benign	0.0034	T;T
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	0.0	N;N
MutationTaster	Benign	0.73	D;D
PrimateAI	Pathogenic	0.96	D
PROVEAN	Benign	0.57	N;N
REVEL	Benign	0.077
Sift	Benign	0.082	T;T
Sift4G	Benign	0.87	T;T
Polyphen		0.44	B;B
Vest4		0.18
MutPred		0.18		Loss of catalytic residue at P120 (P = 0.0094);Loss of catalytic residue at P120 (P = 0.0094);
MVP		0.27
MPC		0.52
ClinPred		0.026	T
GERP RS		3.6
Varity_R		0.099
gMVP		0.098

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

LitVar

Other links and lift over

dbSNP: rs571264557; hg19: chr1-27023252; COSMIC: COSV61373973; COSMIC: COSV61373973;