chr1-26696405-T-C

Position:

• chr1-26696405-T-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_006015.6(ARID1A):​c.2T>C​(p.Met1?) variant causes a start lost change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ARID1A NM_006015.6 start_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.08

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]

LOC124900417 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARID1A	NM_006015.6	c.2T>C	p.Met1?	start_lost	1/20	ENST00000324856.13
LOC124900417	XM_047439473.1	c.1A>G	p.Met1?	start_lost	1/2
ARID1A	NM_139135.4	c.2T>C	p.Met1?	start_lost	1/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARID1A	ENST00000324856.13	c.2T>C	p.Met1?	start_lost	1/20	1	NM_006015.6
ARID1A	ENST00000457599.6	c.2T>C	p.Met1?	start_lost	1/20	5
ARID1A	ENST00000430799.7	c.-13+2788T>C		intron_variant		5		A2
ARID1A	ENST00000637465.1	c.-13+305T>C		intron_variant		5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1130840 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 548472

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Aug 07, 2020

Not observed in large population cohorts (Lek et al., 2016); Initiation codon variant with an unclear effect on protein function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Uncertain	0.0
CADD	Benign	22
DANN	Benign	0.95
DEOGEN2	Benign	0.13	T;.
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Benign	0.42	N
LIST_S2	Uncertain	0.90	D;D
M_CAP	Pathogenic	1.0	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Benign	-1.2	T
MutationTaster	Benign	1.0	D;D
PROVEAN	Benign	-1.0	N;N
REVEL	Uncertain	0.31
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.021	D;D
Polyphen		0.93	P;D
Vest4		0.76
MutPred		0.95		Gain of glycosylation at M1 (P = 0.0154);Gain of glycosylation at M1 (P = 0.0154);
MVP		0.80
ClinPred		0.99	D
GERP RS		3.9
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		3.0
Varity_R		0.95
gMVP		0.63

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: chr1-27022896;