Genetic Variant FOXA1:p.Ala83Thr (chr14-37592537-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The NM_004496.5(FOXA1):c.247G>A(p.Ala83Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.596 in 1,613,240 control chromosomes in the GnomAD database, including 290,586 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 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 0.56 ( 24820 hom., cov: 34)

Exomes 𝑓: 0.60 ( 265766 hom. )

Consequence

FOXA1
NM_004496.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.56

Publications

51 publications found

Variant links:

Genes affected

FOXA1 (HGNC:5021): (forkhead box A1) This gene encodes a member of the forkhead class of DNA-binding proteins. These hepatocyte nuclear factors are transcriptional activators for liver-specific transcripts 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. [provided by RefSeq, Jul 2008]

FOXA1 links:

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ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=8.9052753E-7).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.834 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXA1	NM_004496.5 link	c.247G>A	p.Ala83Thr	missense_variant	Exon 2 of 2	ENST00000250448.5	NP_004487.2	P55317-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
FOXA1	ENST00000250448.5 link	c.247G>A	p.Ala83Thr	missense_variant	Exon 2 of 2	1	NM_004496.5	ENSP00000250448.3	P55317-1
FOXA1	ENST00000545425.2 link	n.362G>A		non_coding_transcript_exon_variant	Exon 2 of 2	2
FOXA1	ENST00000553751.1 link	n.*237G>A		non_coding_transcript_exon_variant	Exon 3 of 3	4		ENSP00000451704.1	G3V4B9
FOXA1	ENST00000553751.1 link	n.*237G>A		3_prime_UTR_variant	Exon 3 of 3	4		ENSP00000451704.1	G3V4B9

Frequencies

GnomAD3 genomes

AF:

0.562

AC:

85433

AN:

152004

Hom.:

24802

Cov.:

show subpopulations

Gnomad AFR

AF:

0.423

Gnomad AMI

AF:

0.728

Gnomad AMR

AF:

0.644

Gnomad ASJ

AF:

0.537

Gnomad EAS

AF:

0.856

Gnomad SAS

AF:

0.565

Gnomad FIN

AF:

0.628

Gnomad MID

AF:

0.547

Gnomad NFE

AF:

0.595

Gnomad OTH

AF:

0.562

GnomAD2 exomes

AF:

0.617

AC:

152220

AN:

246808

AF XY:

0.610

show subpopulations

Gnomad AFR exome

AF:

0.422

Gnomad AMR exome

AF:

0.713

Gnomad ASJ exome

AF:

0.549

Gnomad EAS exome

AF:

0.865

Gnomad FIN exome

AF:

0.631

Gnomad NFE exome

AF:

0.593

Gnomad OTH exome

AF:

0.605

GnomAD4 exome

AF:

0.600

AC:

876657

AN:

1461120

Hom.:

265766

Cov.:

AF XY:

0.598

AC XY:

434684

AN XY:

726786

show subpopulations

African (AFR)

AF:

0.418

AC:

13981

AN:

33466

American (AMR)

AF:

0.707

AC:

31604

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.549

AC:

14352

AN:

26124

East Asian (EAS)

AF:

0.867

AC:

34395

AN:

39686

South Asian (SAS)

AF:

0.561

AC:

48415

AN:

86242

European-Finnish (FIN)

AF:

0.628

AC:

33365

AN:

53108

Middle Eastern (MID)

AF:

0.542

AC:

3128

AN:

5766

European-Non Finnish (NFE)

AF:

0.595

AC:

661562

AN:

1111656

Other (OTH)

AF:

0.594

AC:

35855

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

24563

49126

73690

98253

122816

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18094

36188

54282

72376

90470

<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:

0.562

AC:

85484

AN:

152120

Hom.:

24820

Cov.:

AF XY:

0.566

AC XY:

42103

AN XY:

74368

show subpopulations

African (AFR)

AF:

0.423

AC:

17567

AN:

41530

American (AMR)

AF:

0.644

AC:

9858

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.537

AC:

1866

AN:

3472

East Asian (EAS)

AF:

0.855

AC:

4371

AN:

5110

South Asian (SAS)

AF:

0.564

AC:

2720

AN:

4822

European-Finnish (FIN)

AF:

0.628

AC:

6659

AN:

10608

Middle Eastern (MID)

AF:

0.561

AC:

165

AN:

294

European-Non Finnish (NFE)

AF:

0.595

AC:

40418

AN:

67958

Other (OTH)

AF:

0.567

AC:

1196

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1951

3902

5853

7804

9755

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

730

1460

2190

2920

3650

<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:

0.587

Hom.:

101787

Bravo

AF:

0.564

TwinsUK

AF:

0.581

AC:

2156

ALSPAC

AF:

0.591

AC:

2277

ESP6500AA

AF:

0.441

AC:

1897

ESP6500EA

AF:

0.589

AC:

4870

ExAC

AF:

0.604

AC:

72959

Asia WGS

AF:

0.693

AC:

2407

AN:

3474

EpiCase

AF:

0.575

EpiControl

AF:

0.580

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.77

BayesDel_noAF

Benign

-0.74

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.20

Eigen

Benign

-0.50

Eigen_PC

Benign

-0.38

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.62

MetaRNN

Benign

8.9e-7

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.64

PhyloP100

1.6

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-0.23

REVEL

Benign

0.030

Sift

Uncertain

0.014

Sift4G

Benign

0.40

Polyphen

0.0090

Vest4

0.021

ClinPred

0.0096

GERP RS

3.0

Varity_R

0.072

gMVP

0.60

Mutation Taster

=89/11

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