6-156778948-C-T

Position:

• chr6-156778948-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001374828.1(ARID1B):​c.1268C>T​(p.Ala423Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000218 in 1,282,842 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00010 (0 hom., cov: 29)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: ARID1B NM_001374828.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 2.14

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.02032873).
• BP6: Variant 6-156778948-C-T is Benign according to our data. Variant chr6-156778948-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 235645.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS2: High AC in GnomAd4 at 15 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARID1B	NM_001374828.1	c.1268C>T	p.Ala423Val	missense_variant	1/20	ENST00000636930.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARID1B	ENST00000636930.2	c.1268C>T	p.Ala423Val	missense_variant	1/20	2	NM_001374828.1	A2

Frequencies

GnomAD3 genomes AF: 0.000103 AC: 15 AN: 145190 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.0106

Gnomad AMR AF: 0.0000674

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: 0.0000761

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000114 AC: 13 AN: 1137652 Hom.: 0 Cov.: 35 AF XY: 0.0000128 AC XY: 7 AN XY: 548416

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.0000136

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.000103 AC: 15 AN: 145190 Hom.: 0 Cov.: 29 AF XY: 0.0000845 AC XY: 6 AN XY: 70974

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000674

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000761

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 10, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 21, 2024	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 340 of the ARID1B protein (p.Ala340Val). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the gnomAD database. 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: 235645). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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	Benign	0.28
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	21
DANN	Benign	0.87
DEOGEN2	Benign	0.015	.;T;.;.
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.089	N
LIST_S2	Benign	0.45	T;T;T;T
M_CAP	Pathogenic	0.55	D
MetaRNN	Benign	0.020	T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.0	.;N;N;N
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-0.37	.;N;.;.
REVEL	Benign	0.041
Sift	Benign	0.091	.;T;.;.
Sift4G	Benign	0.099	.;T;.;.
Polyphen		0.24, 0.35	.;B;.;B
Vest4		0.25
MutPred		0.37		.;Gain of catalytic residue at A340 (P = 0.0087);Gain of catalytic residue at A340 (P = 0.0087);Gain of catalytic residue at A340 (P = 0.0087);
MVP		0.12
MPC		0.29
ClinPred		0.14	T
GERP RS		1.4
Varity_R		0.074
gMVP		0.17

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: rs878853084; hg19: chr6-157100082; COSMIC: COSV99034260; COSMIC: COSV99034260;