chr14-58346450-A-T

Variant names:

• chr14-58346450-A-T
• rs1290728413
• NM_002892.4:c.1019A>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP3 BS2

The NM_002892.4(ARID4A):​c.1019A>T​(p.Asp340Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000435 in 1,610,370 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 29)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: ARID4A NM_002892.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.31
• Publications: 0 publications found

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]

TOMM20L-DT (HGNC:55443): (TOMM20L divergent transcript)

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.748
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002892.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARID4A	NM_002892.4	MANE Select	c.1019A>T	p.Asp340Val	missense	Exon 13 of 24	NP_002883.3
	ARID4A	NM_023000.3		c.1019A>T	p.Asp340Val	missense	Exon 13 of 24	NP_075376.2	P29374-2
	ARID4A	NM_023001.3		c.1019A>T	p.Asp340Val	missense	Exon 13 of 23	NP_075377.2	P29374-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARID4A	ENST00000355431.8	TSL:1 MANE Select	c.1019A>T	p.Asp340Val	missense	Exon 13 of 24	ENSP00000347602.3	P29374-1
	ARID4A	ENST00000417477.2	TSL:1	c.53A>T	p.Asp18Val	missense	Exon 3 of 10	ENSP00000416053.2	H7C485
	ARID4A	ENST00000941390.1		c.1019A>T	p.Asp340Val	missense	Exon 13 of 24	ENSP00000611449.1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151990 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000803 AC: 2 AN: 249032 AF XY: 0.00000742

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000343 AC: 5 AN: 1458380 Hom.: 0 Cov.: 29 AF XY: 0.00000413 AC XY: 3 AN XY: 725642

African (AFR) AF: 0.00 AC: 0 AN: 33290

American (AMR) AF: 0.00 AC: 0 AN: 44422

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26028

East Asian (EAS) AF: 0.00 AC: 0 AN: 39322

South Asian (SAS) AF: 0.00 AC: 0 AN: 85966

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53324

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5746

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1110052

Other (OTH) AF: 0.00 AC: 0 AN: 60230

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151990 Hom.: 0 Cov.: 29 AF XY: 0.0000135 AC XY: 1 AN XY: 74228

African (AFR) AF: 0.00 AC: 0 AN: 41398

American (AMR) AF: 0.00 AC: 0 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10528

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68006

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Uncertain	0.096	D
BayesDel_noAF	Uncertain	-0.080
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.57	D
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.065	D
MetaRNN	Pathogenic	0.75	D
MetaSVM	Benign	-0.54	T
MutationAssessor	Benign	1.5	L
PhyloP100		7.3
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-6.9	D
REVEL	Uncertain	0.42
Sift	Uncertain	0.029	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.60
MutPred		0.59		Gain of catalytic residue at L336 (P = 0.0191)
MVP		0.67
MPC		0.64
ClinPred		0.93	D
GERP RS		4.6
Varity_R		0.50
gMVP		0.64
Mutation Taster		=48/52	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1290728413; hg19: chr14-58813168;