Genetic Variant NM_002892.4:c.2335A>G (chr14-58364424-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_002892.4(ARID4A):c.2335A>G(p.Thr779Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.346 in 1,612,356 control chromosomes in the GnomAD database, including 98,589 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.34 ( 9155 hom., cov: 32)

Exomes 𝑓: 0.35 ( 89434 hom. )

Consequence

ARID4A
NM_002892.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0140

Publications

36 publications found

Variant links:

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]

ARID4A links:

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

TOMM20L-DT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=9.797327E-5).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.492 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARID4A	NM_002892.4 link	c.2335A>G	p.Thr779Ala	missense_variant	Exon 20 of 24	ENST00000355431.8	NP_002883.3	P29374-1A0A024R657Q05CG0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARID4A	ENST00000355431.8 link	c.2335A>G	p.Thr779Ala	missense_variant	Exon 20 of 24	1	NM_002892.4	ENSP00000347602.3		P29374-1

Frequencies

GnomAD3 genomes

AF:

0.344

AC:

52205

AN:

151894

Hom.:

9140

Cov.:

show subpopulations

Gnomad AFR

AF:

0.356

Gnomad AMI

AF:

0.224

Gnomad AMR

AF:

0.280

Gnomad ASJ

AF:

0.221

Gnomad EAS

AF:

0.509

Gnomad SAS

AF:

0.300

Gnomad FIN

AF:

0.414

Gnomad MID

AF:

0.222

Gnomad NFE

AF:

0.339

Gnomad OTH

AF:

0.316

GnomAD2 exomes

AF:

0.343

AC:

85558

AN:

249570

AF XY:

0.340

show subpopulations

Gnomad AFR exome

AF:

0.359

Gnomad AMR exome

AF:

0.288

Gnomad ASJ exome

AF:

0.235

Gnomad EAS exome

AF:

0.512

Gnomad FIN exome

AF:

0.415

Gnomad NFE exome

AF:

0.338

Gnomad OTH exome

AF:

0.316

GnomAD4 exome

AF:

0.346

AC:

505394

AN:

1460344

Hom.:

89434

Cov.:

AF XY:

0.345

AC XY:

250337

AN XY:

726388

show subpopulations

African (AFR)

AF:

0.356

AC:

11883

AN:

33364

American (AMR)

AF:

0.284

AC:

12655

AN:

44578

Ashkenazi Jewish (ASJ)

AF:

0.232

AC:

6064

AN:

26108

East Asian (EAS)

AF:

0.534

AC:

21128

AN:

39600

South Asian (SAS)

AF:

0.302

AC:

25932

AN:

85744

European-Finnish (FIN)

AF:

0.417

AC:

22236

AN:

53304

Middle Eastern (MID)

AF:

0.266

AC:

1530

AN:

5754

European-Non Finnish (NFE)

AF:

0.345

AC:

383775

AN:

1111556

Other (OTH)

AF:

0.335

AC:

20191

AN:

60336

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

17329

34659

51988

69318

86647

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

12462

24924

37386

49848

62310

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.344

AC:

52258

AN:

152012

Hom.:

9155

Cov.:

AF XY:

0.345

AC XY:

25631

AN XY:

74316

show subpopulations

African (AFR)

AF:

0.356

AC:

14759

AN:

41448

American (AMR)

AF:

0.280

AC:

4281

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.221

AC:

767

AN:

3472

East Asian (EAS)

AF:

0.508

AC:

2628

AN:

5170

South Asian (SAS)

AF:

0.301

AC:

1452

AN:

4824

European-Finnish (FIN)

AF:

0.414

AC:

4356

AN:

10512

Middle Eastern (MID)

AF:

0.231

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.339

AC:

23066

AN:

67976

Other (OTH)

AF:

0.320

AC:

677

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1788

3576

5365

7153

8941

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

516

1032

1548

2064

2580

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.337

Hom.:

39079

Bravo

AF:

0.332

TwinsUK

AF:

0.345

AC:

1279

ALSPAC

AF:

0.345

AC:

1331

ESP6500AA

AF:

0.342

AC:

1506

ESP6500EA

AF:

0.330

AC:

2835

ExAC

AF:

0.344

AC:

41785

Asia WGS

AF:

0.411

AC:

1429

AN:

3474

EpiCase

AF:

0.312

EpiControl

AF:

0.312

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.058

BayesDel_addAF

Benign

-0.74

BayesDel_noAF

Benign

-0.70

CADD

Benign

5.1

(source)

DANN

Benign

0.42

DEOGEN2

Benign

0.042

T;.;.;.;T

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.0067

LIST_S2

Benign

0.029

T;T;T;.;T

MetaRNN

Benign

0.000098

T;T;T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

-0.34

N;N;N;N;.

PhyloP100

-0.014

PrimateAI

Benign

0.23

PROVEAN

Benign

-0.35

N;N;N;N;N

REVEL

Benign

0.040

Sift

Benign

1.0

T;T;T;T;T

Sift4G

Benign

0.78

T;T;T;T;T

Polyphen

0.0

B;B;B;B;.

Vest4

0.028

MPC

0.10

ClinPred

0.00030

GERP RS

1.5

Varity_R

0.027

gMVP

0.12

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over