chr20-22582013-G-A

Position:

chr20-22582013-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_021784.5(FOXA2):c.1229C>T(p.Ala410Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000372 in 1,614,106 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000033 ( 0 hom. )

Consequence

FOXA2
NM_021784.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 6.87

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 Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.32686895).

BS2

High AC in GnomAd4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
FOXA2	NM_021784.5 linkuse as main transcript	c.1229C>T	p.Ala410Val	missense_variant	2/2	ENST00000419308.7	NP_068556.2
FOXA2	NM_153675.3 linkuse as main transcript	c.1211C>T	p.Ala404Val	missense_variant	3/3		NP_710141.1
FOXA2	XM_047440133.1 linkuse as main transcript	c.1211C>T	p.Ala404Val	missense_variant	3/3		XP_047296089.1
FOXA2	XM_047440134.1 linkuse as main transcript	c.1121C>T	p.Ala374Val	missense_variant	2/2		XP_047296090.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FOXA2	ENST00000419308.7 linkuse as main transcript	c.1229C>T	p.Ala410Val	missense_variant	2/2	1	NM_021784.5	ENSP00000400341	P4	Q9Y261-2
FOXA2	ENST00000377115.4 linkuse as main transcript	c.1211C>T	p.Ala404Val	missense_variant	3/3	1		ENSP00000366319	A1	Q9Y261-1

Frequencies

GnomAD3 genomes

AF:

0.0000788

AC:

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000392

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.0000756

AC:

AN:

251354

Hom.:

AF XY:

0.0000589

AC XY:

AN XY:

135866

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000463

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:

0.00000880

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.0000328

AC:

AN:

1461888

Hom.:

Cov.:

AF XY:

0.0000289

AC XY:

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000581

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:

0.0000162

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.0000788

AC:

AN:

152218

Hom.:

Cov.:

AF XY:

0.0000941

AC XY:

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000392

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00143

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.000140

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 12, 2022

The c.1229C>T (p.A410V) alteration is located in exon 2 (coding exon 2) of the FOXA2 gene. This alteration results from a C to T substitution at nucleotide position 1229, causing the alanine (A) at amino acid position 410 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 02, 2022

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. 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: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with FOXA2-related conditions. This variant is present in population databases (rs201279073, gnomAD 0.04%), and has an allele count higher than expected for a pathogenic variant. This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 410 of the FOXA2 protein (p.Ala410Val). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.43

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.51

.;D

Eigen

Uncertain

0.33

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Benign

0.057

MetaRNN

Benign

0.33

T;T

MetaSVM

Benign

-0.75

MutationAssessor

Benign

1.9

.;L

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-1.8

.;N

REVEL

Benign

0.22

Sift

Uncertain

0.0090

.;D

Sift4G

Benign

0.10

T;T

Polyphen

0.34

.;B

Vest4

0.45

MutPred

0.54

.;Gain of sheet (P = 0.0028);

MVP

0.70

ClinPred

0.14

GERP RS

4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.22

gMVP

0.46

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