Variant 20-22582142-T-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_021784.5(FOXA2):c.1100A>C(p.Glu367Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000197 in 1,577,024 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 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000020 ( 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 Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.11932984).

BS2

High AC in GnomAdExome4 at 28 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
FOXA2	NM_021784.5 linkuse as main transcript	c.1100A>C	p.Glu367Ala	missense_variant	2/2	ENST00000419308.7	NP_068556.2
FOXA2	NM_153675.3 linkuse as main transcript	c.1082A>C	p.Glu361Ala	missense_variant	3/3		NP_710141.1
FOXA2	XM_047440133.1 linkuse as main transcript	c.1082A>C	p.Glu361Ala	missense_variant	3/3		XP_047296089.1
FOXA2	XM_047440134.1 linkuse as main transcript	c.992A>C	p.Glu331Ala	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.1100A>C	p.Glu367Ala	missense_variant	2/2	1	NM_021784.5	ENSP00000400341	P4	Q9Y261-2
FOXA2	ENST00000377115.4 linkuse as main transcript	c.1082A>C	p.Glu361Ala	missense_variant	3/3	1		ENSP00000366319	A1	Q9Y261-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000596

AC:

AN:

184662

Hom.:

AF XY:

0.0000709

AC XY:

AN XY:

98782

show subpopulations

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 SAS exome

AF:

0.000424

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000197

AC:

AN:

1424758

Hom.:

Cov.:

AF XY:

0.0000255

AC XY:

AN XY:

705320

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000279

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000847

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152266

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74450

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000622

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.0000592

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 20, 2023

The c.1100A>C (p.E367A) alteration is located in exon 2 (coding exon 2) of the FOXA2 gene. This alteration results from a A to C substitution at nucleotide position 1100, causing the glutamic acid (E) at amino acid position 367 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.13

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.40

.;T

Eigen

Uncertain

0.24

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.87

D;D

M_CAP

Pathogenic

0.30

MetaRNN

Benign

0.12

T;T

MetaSVM

Uncertain

-0.13

MutationAssessor

Benign

1.3

.;L

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-1.8

N;N

REVEL

Uncertain

0.33

Sift

Benign

0.067

T;T

Sift4G

Benign

0.30

T;T

Polyphen

0.82

.;P

Vest4

0.33

MutPred

0.20

.;Loss of solvent accessibility (P = 0.0442);

MVP

0.64

ClinPred

0.14

GERP RS

4.3

Varity_R

0.12

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