rs1276300860

Variant names:

• chr6-156778680-T-C
• rs1276300860
• NM_001374828.1:c.1000T>C

Your query was ambiguous. Multiple possible variants found:

• chr6-156778680-T-C
• chr6-156778680-T-G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001374828.1(ARID1B):​c.1000T>C​(p.Cys334Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C334W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ARID1B NM_001374828.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.40
• Publications: 0 publications found

Genes affected

ARID1B (HGNC:18040): (AT-rich interaction domain 1B) This locus encodes an AT-rich DNA interacting domain-containing protein. The encoded protein is a component of the SWI/SNF chromatin remodeling complex and may play a role in cell-cycle activation. The protein encoded by this locus is similar to AT-rich interactive domain-containing protein 1A. These two proteins function as alternative, mutually exclusive ARID-subunits of the SWI/SNF complex. The associated complexes play opposing roles. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2016]

ARID1B Gene-Disease associations (from GenCC):

• Coffin-Siris syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, Illumina, ClinGen
• Coffin-Siris syndrome 1

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

ENSG00000296922 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31538796).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARID1B	NM_001374828.1	c.1000T>C	p.Cys334Arg	missense_variant	Exon 1 of 20	ENST00000636930.2	NP_001361757.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARID1B	ENST00000636930.2	c.1000T>C	p.Cys334Arg	missense_variant	Exon 1 of 20	2	NM_001374828.1	ENSP00000490491.2

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1354090 Hom.: 0 Cov.: 37 AF XY: 0.00 AC XY: 0 AN XY: 668630

African (AFR) AF: 0.00 AC: 0 AN: 28696

American (AMR) AF: 0.00 AC: 0 AN: 32874

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23688

East Asian (EAS) AF: 0.00 AC: 0 AN: 31838

South Asian (SAS) AF: 0.00 AC: 0 AN: 76444

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42968

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5350

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1056574

Other (OTH) AF: 0.00 AC: 0 AN: 55658

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Nov 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 251 of the ARID1B protein (p.Cys251Arg). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ARID1B-related conditions. ClinVar contains an entry for this variant (Variation ID: 2915767). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt ARID1B protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Benign	-0.096	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	19
DANN	Benign	0.82
DEOGEN2	Benign	0.026	.;T;.;.
Eigen	Benign	-0.084
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.70	T;T;T;T
M_CAP	Pathogenic	0.85	D
MetaRNN	Benign	0.32	T;T;T;T
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	1.1	.;L;L;L
PhyloP100		1.4
PrimateAI	Pathogenic	0.95	D
PROVEAN	Benign	-1.5	.;N;.;.
REVEL	Benign	0.13
Sift	Uncertain	0.0030	.;D;.;.
Sift4G	Uncertain	0.029	.;D;.;.
Polyphen		0.94, 0.96	.;P;.;D
Vest4		0.22
MutPred		0.40		.;Gain of MoRF binding (P = 0.0144);Gain of MoRF binding (P = 0.0144);Gain of MoRF binding (P = 0.0144);
MVP		0.068
MPC		0.52
ClinPred		0.46	T
GERP RS		1.5
Varity_R		0.70
gMVP		0.30
Mutation Taster		=57/43	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: rs1276300860; hg19: chr6-157099814;