rs2035018997

Variant names:

• chr14-58359132-G-T
• rs2035018997
• NM_002892.4:c.1854G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_002892.4(ARID4A):​c.1854G>T​(p.Arg618Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000014 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ARID4A NM_002892.4 missense, splice_region
• Scores: Splicing: ADA: 0.6647
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.980
• 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: Uncertain_significance. The variant received 0 ACMG points.

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.1854G>T	p.Arg618Ser	missense splice_region	Exon 18 of 24	NP_002883.3
	ARID4A	NM_023000.3		c.1854G>T	p.Arg618Ser	missense splice_region	Exon 18 of 24	NP_075376.2	P29374-2
	ARID4A	NM_023001.3		c.1854G>T	p.Arg618Ser	missense splice_region	Exon 18 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.1854G>T	p.Arg618Ser	missense splice_region	Exon 18 of 24	ENSP00000347602.3	P29374-1
	ARID4A	ENST00000417477.2	TSL:1	c.888G>T	p.Arg296Ser	missense splice_region	Exon 8 of 10	ENSP00000416053.2	H7C485
	ARID4A	ENST00000941390.1		c.1854G>T	p.Arg618Ser	missense splice_region	Exon 18 of 24	ENSP00000611449.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 140374 Hom.: 0 Cov.: 30

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000138 AC: 18 AN: 1306576 Hom.: 0 Cov.: 33 AF XY: 0.0000107 AC XY: 7 AN XY: 653438

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000360 AC: 1 AN: 27774

American (AMR) AF: 0.00 AC: 0 AN: 30302

Ashkenazi Jewish (ASJ) AF: 0.0000436 AC: 1 AN: 22932

East Asian (EAS) AF: 0.00 AC: 0 AN: 37538

South Asian (SAS) AF: 0.0000132 AC: 1 AN: 75752

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51812

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4272

European-Non Finnish (NFE) AF: 0.0000150 AC: 15 AN: 1001950

Other (OTH) AF: 0.00 AC: 0 AN: 54244

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 140454 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 67530

African (AFR) AF: 0.00 AC: 0 AN: 37132

American (AMR) AF: 0.00 AC: 0 AN: 13776

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3400

East Asian (EAS) AF: 0.00 AC: 0 AN: 4918

South Asian (SAS) AF: 0.00 AC: 0 AN: 4506

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7542

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 252

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66118

Other (OTH) AF: 0.00 AC: 0 AN: 1920

Alfa AF: 0.00 Hom.: 0

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	1.0
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.17
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.63	D
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.056	D
MetaRNN	Uncertain	0.62	D
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	1.9	L
PhyloP100		0.98
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-5.1	D
REVEL	Uncertain	0.41
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.037	D
Polyphen		1.0	D
Vest4		0.93
MutPred		0.52		Gain of catalytic residue at W615 (P = 2e-04)
MVP		0.88
MPC		0.57
ClinPred		1.0	D
GERP RS		4.0
Varity_R		0.93
gMVP		0.64
Mutation Taster		=10/90	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.66
dbscSNV1_RF	Benign	0.62
SpliceAI score (max)		0.050		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: rs2035018997; hg19: chr14-58825850;