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

Variant summary

Our verdict is Benign. Variant got -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. 12/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

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

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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

GnomAD3 exomes

AF:

0.617

AC:

152220

AN:

246808

Hom.:

48149

AF XY:

0.610

AC XY:

81792

AN XY:

134100

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 SAS exome

AF:

0.559

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

Gnomad4 AFR exome

AF:

0.418

Gnomad4 AMR exome

AF:

0.707

Gnomad4 ASJ exome

AF:

0.549

Gnomad4 EAS exome

AF:

0.867

Gnomad4 SAS exome

AF:

0.561

Gnomad4 FIN exome

AF:

0.628

Gnomad4 NFE exome

AF:

0.595

Gnomad4 OTH exome

AF:

0.594

GnomAD4 genome

AF:

0.562

AC:

85484

AN:

152120

Hom.:

24820

Cov.:

AF XY:

0.566

AC XY:

42103

AN XY:

74368

show subpopulations

Gnomad4 AFR

AF:

0.423

Gnomad4 AMR

AF:

0.644

Gnomad4 ASJ

AF:

0.537

Gnomad4 EAS

AF:

0.855

Gnomad4 SAS

AF:

0.564

Gnomad4 FIN

AF:

0.628

Gnomad4 NFE

AF:

0.595

Gnomad4 OTH

AF:

0.567

Alfa

AF:

0.590

Hom.:

49797

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

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

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over