20-22581969-G-T

Position:

chr20-22581969-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_021784.5(FOXA2):c.1273C>A(p.Pro425Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00246 in 1,613,430 control chromosomes in the GnomAD database, including 121 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0046 ( 22 hom., cov: 32)

Exomes 𝑓: 0.0022 ( 99 hom. )

Consequence

FOXA2
NM_021784.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 9.84

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0033374727).

BP6

Variant 20-22581969-G-T is Benign according to our data. Variant chr20-22581969-G-T is described in ClinVar as [Benign]. Clinvar id is 769996.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.066 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
FOXA2	NM_021784.5 linkuse as main transcript	c.1273C>A	p.Pro425Thr	missense_variant	2/2	ENST00000419308.7	NP_068556.2
FOXA2	NM_153675.3 linkuse as main transcript	c.1255C>A	p.Pro419Thr	missense_variant	3/3		NP_710141.1
FOXA2	XM_047440133.1 linkuse as main transcript	c.1255C>A	p.Pro419Thr	missense_variant	3/3		XP_047296089.1
FOXA2	XM_047440134.1 linkuse as main transcript	c.1165C>A	p.Pro389Thr	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.1273C>A	p.Pro425Thr	missense_variant	2/2	1	NM_021784.5	ENSP00000400341	P4	Q9Y261-2
FOXA2	ENST00000377115.4 linkuse as main transcript	c.1255C>A	p.Pro419Thr	missense_variant	3/3	1		ENSP00000366319	A1	Q9Y261-1

Frequencies

GnomAD3 genomes

AF:

0.00461

AC:

701

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00118

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0413

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00765

GnomAD3 exomes

AF:

0.00997

AC:

2504

AN:

251102

Hom.:

AF XY:

0.00722

AC XY:

980

AN XY:

135694

show subpopulations

Gnomad AFR exome

AF:

0.000739

Gnomad AMR exome

AF:

0.0701

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:

0.0000705

Gnomad OTH exome

AF:

0.00963

GnomAD4 exome

AF:

0.00223

AC:

3259

AN:

1461094

Hom.:

Cov.:

AF XY:

0.00181

AC XY:

1316

AN XY:

726668

show subpopulations

Gnomad4 AFR exome

AF:

0.000807

Gnomad4 AMR exome

AF:

0.0680

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:

0.0000261

Gnomad4 OTH exome

AF:

0.00270

GnomAD4 genome

AF:

0.00464

AC:

707

AN:

152336

Hom.:

Cov.:

AF XY:

0.00494

AC XY:

368

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.00118

Gnomad4 AMR

AF:

0.0417

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00757

Alfa

AF:

0.000270

Hom.:

Bravo

AF:

0.00849

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00751

AC:

912

Asia WGS

AF:

0.00318

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

FOXA2-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 18, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Uncertain

0.43

.;T

Eigen

Benign

-0.11

Eigen_PC

Benign

0.035

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.85

D;D

MetaRNN

Benign

0.0033

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.7

.;L

MutationTaster

Benign

0.68

D;D;D

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-2.3

.;N

REVEL

Benign

0.10

Sift

Benign

0.12

.;T

Sift4G

Benign

0.18

T;T

Polyphen

0.0040

.;B

Vest4

0.68

MVP

0.57

ClinPred

0.089

GERP RS

4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.13

gMVP

0.42

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