rs797045264

Positions:

• chr1-26779036-T-A
• chr1-26779036-T-C
• chr1-26779036-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM5

The NM_006015.6(ARID1A):​c.5138T>A​(p.Leu1713Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L1713P) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ARID1A NM_006015.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.53

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-26779036-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 210260.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARID1A	NM_006015.6	c.5138T>A	p.Leu1713Gln	missense_variant	20/20	ENST00000324856.13
ARID1A	NM_139135.4	c.4487T>A	p.Leu1496Gln	missense_variant	20/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARID1A	ENST00000324856.13	c.5138T>A	p.Leu1713Gln	missense_variant	20/20	1	NM_006015.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.80	.;D;.;.;T
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D
M_CAP	Benign	0.055	D
MetaRNN	Uncertain	0.72	D;D;D;D;D
MetaSVM	Benign	-0.90	T
MutationAssessor	Uncertain	2.8	.;M;.;.;.
MutationTaster	Benign	1.0	D;D;D;N
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-5.5	.;D;D;D;.
REVEL	Uncertain	0.45
Sift	Pathogenic	0.0	.;D;D;D;.
Sift4G	Pathogenic	0.0	.;D;D;D;.
Polyphen		0.96, 1.0, 1.0	.;D;D;D;.
Vest4		0.91, 0.94, 0.88
MutPred		0.37		.;Gain of catalytic residue at L1713 (P = 0.013);.;.;.;
MVP		0.84
MPC		1.5
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.93
gMVP		0.95

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-27105527; COSMIC: COSV61380164; COSMIC: COSV61380164;