1-26780416-A-T

Variant names:

• chr1-26780416-A-T
• rs1553153783
• NM_006015.6:c.6518A>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP5_Moderate

The NM_006015.6(ARID1A):​c.6518A>T​(p.Asn2173Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N2173S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ARID1A NM_006015.6 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.01
• Publications: 0 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: Orphanet, ClinGen
• intellectual disability, autosomal dominant 14

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Illumina, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-26780416-A-T is Pathogenic according to our data. Variant chr1-26780416-A-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 917881.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARID1A	NM_006015.6	c.6518A>T	p.Asn2173Ile	missense_variant	Exon 20 of 20	ENST00000324856.13	NP_006006.3
ARID1A	NM_139135.4	c.5867A>T	p.Asn1956Ile	missense_variant	Exon 20 of 20		NP_624361.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARID1A	ENST00000324856.13	c.6518A>T	p.Asn2173Ile	missense_variant	Exon 20 of 20	1	NM_006015.6	ENSP00000320485.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Intellectual disability, autosomal dominant 14 Pathogenic:1

-

Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Using trio exome sequencing and analysis of the genes with the ten highest PEDIA values ​​(PMID: 31164752), the patient was able to detect a probably pathogenic missense variant in exon 12 of the AR / D1A gene (NM_006015). This variant could not be demonstrated in the parents, which is why it is highly likely that the patient was newly created (de novo). The name of the variant is: c.6518A> T; p.Asn2173Ile). This variant has not yet been recorded in population-related and phenotype-related databases. Another base exchange at the same nucleotide position (c.6518A> G; p. (Asn2173Ser)) is listed in the phenotype-related database ClinVar as a variant of unclear functional relevance. In these databases and in publications, predominantly truncating variants in the ARID1A gene are considered pathogenic. The mutation prediction programs MutationTaster, SIFT and PolyPhen-2 assess the variant as pathogenic; the CADD score is 26.2. It is a moderately conserved amino acid that lies in an Armadillo-type fold. The ACMG classification of the variant is: probably pathogenic (Class 4: PS2, PM2, PP3, BP1 (strong). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Pathogenic	28
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.42	.;T;.;.;T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D
M_CAP	Benign	0.035	D
MetaRNN	Uncertain	0.69	D;D;D;D;D
MetaSVM	Benign	-0.41	T
MutationAssessor	Uncertain	2.3	.;M;.;.;.
PhyloP100		9.0
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-6.4	.;D;D;D;.
REVEL	Uncertain	0.36
Sift	Uncertain	0.0050	.;D;D;D;.
Sift4G	Pathogenic	0.0010	.;D;D;D;.
Polyphen		0.99, 0.99, 1.0	.;D;D;D;.
Vest4		0.87, 0.83, 0.86
MutPred		0.37		.;Loss of catalytic residue at N2173 (P = 0.0024);.;.;.;
MVP		0.69
MPC		1.6
ClinPred		0.99	D
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.88
gMVP		0.86
Mutation Taster		=56/44	disease causing (ClinVar)

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: rs1553153783; hg19: chr1-27106907;