1-26773716-C-T

Position:

• chr1-26773716-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_006015.6(ARID1A):​c.4003C>T​(p.Arg1335Ter) variant causes a stop gained, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ARID1A NM_006015.6 stop_gained, splice_region
• Scores: Splicing: ADA: 0.1005
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 2.05

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 Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-26773716-C-T is Pathogenic according to our data. Variant chr1-26773716-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 30294.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-26773716-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARID1A	NM_006015.6	c.4003C>T	p.Arg1335Ter	stop_gained, splice_region_variant	16/20	ENST00000324856.13	NP_006006.3
ARID1A	NM_139135.4	c.4003C>T	p.Arg1335Ter	stop_gained, splice_region_variant	16/20		NP_624361.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARID1A	ENST00000324856.13	c.4003C>T	p.Arg1335Ter	stop_gained, splice_region_variant	16/20	1	NM_006015.6	ENSP00000320485

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Coffin-Siris syndrome 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn

-

- -

Intellectual disability, autosomal dominant 14 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 18, 2012

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	38
DANN	Uncertain	1.0
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.87	D
MutationTaster	Benign	1.0	A;A;A;D
Vest4		0.93, 0.93, 0.97, 0.95
ClinPred		1.0	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.10
dbscSNV1_RF	Benign	0.46
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: rs387906846; hg19: chr1-27100207; COSMIC: COSV61371872; COSMIC: COSV61371872;