20-22582933-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_021784.5(FOXA2):c.309C>T(p.Ala103Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0502 in 1,528,470 control chromosomes in the GnomAD database, including 3,153 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.080 ( 733 hom., cov: 33)

Exomes 𝑓: 0.047 ( 2420 hom. )

Consequence

FOXA2
NM_021784.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.643

Publications

8 publications found

Variant links:

Genes affected

FOXA2 (HGNC:5022): (forkhead box A2) This gene encodes a member of the forkhead class of DNA-binding proteins. These hepatocyte nuclear factors are transcriptional activators for liver-specific genes such as albumin and transthyretin, and they also interact with chromatin. Similar family members in mice have roles in the regulation of metabolism and in the differentiation of the pancreas and liver. This gene has been linked to sporadic cases of maturity-onset diabetes of the young. Transcript variants encoding different isoforms have been identified for this gene. [provided by RefSeq, Oct 2008]

FOXA2 Gene-Disease associations (from GenCC):

combined pituitary hormone deficiencies, genetic form
Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: ClinGen, Orphanet

FOXA2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.62).

BP6

Variant 20-22582933-G-A is Benign according to our data. Variant chr20-22582933-G-A is described in ClinVar as Benign. ClinVar VariationId is 1569424.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.643 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.157 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021784.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXA2	NM_021784.5	MANE Select	c.309C>T	p.Ala103Ala	synonymous	Exon 2 of 2	NP_068556.2
	FOXA2	NM_153675.3		c.291C>T	p.Ala97Ala	synonymous	Exon 3 of 3	NP_710141.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXA2	ENST00000419308.7	TSL:1 MANE Select	c.309C>T	p.Ala103Ala	synonymous	Exon 2 of 2	ENSP00000400341.3
	FOXA2	ENST00000377115.4	TSL:1	c.291C>T	p.Ala97Ala	synonymous	Exon 3 of 3	ENSP00000366319.4

Frequencies

GnomAD3 genomes

AF:

0.0799

AC:

12133

AN:

151914

Hom.:

727

Cov.:

show subpopulations

Gnomad AFR

AF:

0.160

Gnomad AMI

AF:

0.127

Gnomad AMR

AF:

0.0453

Gnomad ASJ

AF:

0.0908

Gnomad EAS

AF:

0.157

Gnomad SAS

AF:

0.0870

Gnomad FIN

AF:

0.0233

Gnomad MID

AF:

0.0350

Gnomad NFE

AF:

0.0401

Gnomad OTH

AF:

0.0786

GnomAD2 exomes

AF:

0.0712

AC:

9347

AN:

131320

AF XY:

0.0710

show subpopulations

Gnomad AFR exome

AF:

0.225

Gnomad AMR exome

AF:

0.0342

Gnomad ASJ exome

AF:

0.0989

Gnomad EAS exome

AF:

0.180

Gnomad FIN exome

AF:

0.0258

Gnomad NFE exome

AF:

0.0468

Gnomad OTH exome

AF:

0.0658

GnomAD4 exome

AF:

0.0469

AC:

64568

AN:

1376450

Hom.:

2420

Cov.:

AF XY:

0.0481

AC XY:

32709

AN XY:

680274

show subpopulations

African (AFR)

AF:

0.174

AC:

5175

AN:

29662

American (AMR)

AF:

0.0329

AC:

1069

AN:

32460

Ashkenazi Jewish (ASJ)

AF:

0.0913

AC:

2136

AN:

23400

East Asian (EAS)

AF:

0.183

AC:

6439

AN:

35214

South Asian (SAS)

AF:

0.0838

AC:

6441

AN:

76902

European-Finnish (FIN)

AF:

0.0274

AC:

1126

AN:

41020

Middle Eastern (MID)

AF:

0.0604

AC:

302

AN:

4996

European-Non Finnish (NFE)

AF:

0.0355

AC:

38234

AN:

1075730

Other (OTH)

AF:

0.0639

AC:

3646

AN:

57066

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.530

Heterozygous variant carriers

3758

7516

11275

15033

18791

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1602

3204

4806

6408

8010

<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:

0.0800

AC:

12161

AN:

152020

Hom.:

733

Cov.:

AF XY:

0.0792

AC XY:

5888

AN XY:

74322

show subpopulations

African (AFR)

AF:

0.161

AC:

6663

AN:

41492

American (AMR)

AF:

0.0452

AC:

690

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.0908

AC:

315

AN:

3470

East Asian (EAS)

AF:

0.157

AC:

807

AN:

5132

South Asian (SAS)

AF:

0.0869

AC:

419

AN:

4822

European-Finnish (FIN)

AF:

0.0233

AC:

246

AN:

10568

Middle Eastern (MID)

AF:

0.0308

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0401

AC:

2727

AN:

67942

Other (OTH)

AF:

0.0802

AC:

169

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

562

1123

1685

2246

2808

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

136

272

408

544

680

<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:

0.0361

Hom.:

Bravo

AF:

0.0849

Asia WGS

AF:

0.148

AC:

508

AN:

3452

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

FOXA2-related disorder

Benign:1

Sep 17, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.62

CADD

Benign

5.1

(source)

DANN

Benign

0.94

PhyloP100

-0.64

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over