14-58361004-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002892.4(ARID4A):c.2042A>G(p.Tyr681Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,806 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: ARID4A NM_002892.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.86

Genes affected

ARID4A (HGNC:9885): (AT-rich interaction domain 4A) The protein encoded by this gene is a ubiquitously expressed nuclear protein. It binds directly, with several other proteins, to retinoblastoma protein (pRB) which regulates cell proliferation. pRB represses transcription by recruiting the encoded protein. This protein, in turn, serves as a bridging molecule to recruit HDACs and, in addition, provides a second HDAC-independent repression function. The encoded protein possesses transcriptional repression activity. Multiple alternatively spliced transcripts have been observed for this gene, although not all transcript variants have been fully described. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10024899).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARID4A	NM_002892.4	c.2042A>G	p.Tyr681Cys	missense_variant	19/24	ENST00000355431.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARID4A	ENST00000355431.8	c.2042A>G	p.Tyr681Cys	missense_variant	19/24	1	NM_002892.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251346 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135844

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461806 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727196

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: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 11, 2022

The c.2042A>G (p.Y681C) alteration is located in exon 19 (coding exon 18) of the ARID4A gene. This alteration results from a A to G substitution at nucleotide position 2042, causing the tyrosine (Y) at amino acid position 681 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.049
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.47
Cadd	Benign	19
Dann	Uncertain	0.98
DEOGEN2	Benign	0.042	T;.;.;.;T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.62	D
LIST_S2	Uncertain	0.88	D;D;D;.;D
M_CAP	Benign	0.0021	T
MetaRNN	Benign	0.10	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L;L;L;L;.
MutationTaster	Benign	0.92	N;N;N;N
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.92	N;N;N;N;N
REVEL	Benign	0.11
Sift	Benign	0.18	T;T;T;T;T
Sift4G	Benign	0.18	T;T;T;T;T
Polyphen		0.0	B;B;B;B;.
Vest4		0.25
MutPred		0.26		Gain of catalytic residue at M679 (P = 0);Gain of catalytic residue at M679 (P = 0);Gain of catalytic residue at M679 (P = 0);Gain of catalytic residue at M679 (P = 0);.;
MVP		0.40
MPC		0.14
ClinPred		0.24	T
GERP RS		1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.038
gMVP		0.079

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: rs763120468; hg19: chr14-58827722;