Genetic Variant FOXA1:p.Gly327Arg (chr14-37591805-C-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_004496.5(FOXA1):c.979G>A(p.Gly327Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000765 in 1,307,750 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. G327V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.6e-7 ( 0 hom. )

Consequence

FOXA1
NM_004496.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.51

Publications

0 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: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3703997).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004496.5. 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
	FOXA1	NM_004496.5	MANE Select	c.979G>A	p.Gly327Arg	missense	Exon 2 of 2	NP_004487.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXA1	ENST00000250448.5	TSL:1 MANE Select	c.979G>A	p.Gly327Arg	missense	Exon 2 of 2	ENSP00000250448.3	P55317-1
	FOXA1	ENST00000545425.2	TSL:2	n.1094G>A		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

65794

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

7.65e-7

AC:

AN:

1307750

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

637018

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

28628

American (AMR)

AF:

0.00

AC:

AN:

21744

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19324

East Asian (EAS)

AF:

0.00

AC:

AN:

35202

South Asian (SAS)

AF:

0.00

AC:

AN:

64260

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37468

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4634

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1042382

Other (OTH)

AF:

0.0000185

AC:

AN:

54108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Uncertain

0.033

BayesDel_noAF

Benign

-0.19

CADD

Benign

(source)

DANN

Uncertain

0.97

DEOGEN2

Benign

0.26

Eigen

Benign

-0.043

Eigen_PC

Benign

0.0012

FATHMM_MKL

Benign

0.54

LIST_S2

Benign

0.70

M_CAP

Pathogenic

0.90

MetaRNN

Benign

0.37

MetaSVM

Benign

-0.29

MutationAssessor

Benign

1.4

PhyloP100

1.5

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

-0.27

REVEL

Benign

0.24

Sift

Benign

0.15

Sift4G

Benign

0.53

Polyphen

0.97

Vest4

0.24

MutPred

0.36

Gain of catalytic residue at G327 (P = 0.0011)

MVP

0.79

ClinPred

0.58

GERP RS

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.084

gMVP

0.37

Mutation Taster

=70/30

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over