20-22582124-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_021784.5(FOXA2):c.1118A>T(p.Glu373Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000139 in 1,443,564 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E373D) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

FOXA2
NM_021784.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.20

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
FOXA2	NM_021784.5 linkuse as main transcript	c.1118A>T	p.Glu373Val	missense_variant	2/2	ENST00000419308.7
FOXA2	NM_153675.3 linkuse as main transcript	c.1100A>T	p.Glu367Val	missense_variant	3/3
FOXA2	XM_047440133.1 linkuse as main transcript	c.1100A>T	p.Glu367Val	missense_variant	3/3
FOXA2	XM_047440134.1 linkuse as main transcript	c.1010A>T	p.Glu337Val	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FOXA2	ENST00000419308.7 linkuse as main transcript	c.1118A>T	p.Glu373Val	missense_variant	2/2	1	NM_021784.5	P4	Q9Y261-2
FOXA2	ENST00000377115.4 linkuse as main transcript	c.1100A>T	p.Glu367Val	missense_variant	3/3	1		A1	Q9Y261-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000946

AC:

AN:

211478

Hom.:

AF XY:

0.00

AC XY:

AN XY:

114144

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000676

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS 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:

0.00000139

AC:

AN:

1443564

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

716408

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000489

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000166

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Feb 04, 2022

This sequence change replaces glutamic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 373 of the FOXA2 protein (p.Glu373Val). This variant is present in population databases (rs767212576, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with FOXA2-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.90

BayesDel_addAF

Benign

-0.044

BayesDel_noAF

Benign

-0.12

Cadd

Pathogenic

Dann

Uncertain

0.98

Eigen

Benign

0.022

Eigen_PC

Benign

0.11

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.90

D;D

M_CAP

Pathogenic

0.55

MetaRNN

Uncertain

0.48

T;T

MetaSVM

Uncertain

0.015

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.88

REVEL

Uncertain

0.35

Sift4G

Uncertain

0.011

D;D

Polyphen

0.26

.;B

Vest4

0.57

MutPred

0.21

.;Loss of phosphorylation at Y370 (P = 0.0933);

MVP

0.76

ClinPred

0.94

GERP RS

3.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.24

gMVP

0.62

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over