20-22581969-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 9.84

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]

ACMG classification

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	UniProt
FOXA2	NM_021784.5	c.1273C>A	p.Pro425Thr	missense_variant	2/2	ENST00000419308.7
FOXA2	NM_153675.3	c.1255C>A	p.Pro419Thr	missense_variant	3/3
FOXA2	XM_047440133.1	c.1255C>A	p.Pro419Thr	missense_variant	3/3
FOXA2	XM_047440134.1	c.1165C>A	p.Pro389Thr	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FOXA2	ENST00000419308.7	c.1273C>A	p.Pro425Thr	missense_variant	2/2	1	NM_021784.5	P4
FOXA2	ENST00000377115.4	c.1255C>A	p.Pro419Thr	missense_variant	3/3	1		A1

Frequencies

GnomAD3 genomes AF: 0.00461 AC: 701 AN: 152218 Hom.: 22 Cov.: 32

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.: 92 AF XY: 0.00722 AC XY: 980 AN XY: 135694

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.: 99 Cov.: 30 AF XY: 0.00181 AC XY: 1316 AN XY: 726668

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.: 22 Cov.: 32 AF XY: 0.00494 AC XY: 368 AN XY: 74492

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.: 0

Bravo AF: 0.00849

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00751 AC: 912

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

FOXA2-related disorder Benign:1

Benign, criteria provided, single submitter

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). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.48
Cadd	Benign	23
Dann	Benign	0.93
Eigen	Benign	-0.11
Eigen_PC	Benign	0.035
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.85	D;D
MetaRNN	Benign	0.0033	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.68	D;D;D
PrimateAI	Uncertain	0.61	T
REVEL	Benign	0.10
Sift4G	Benign	0.18	T;T
Polyphen		0.0040	.;B
Vest4		0.68
MVP		0.57
ClinPred		0.089	T
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

Other links and lift over

dbSNP: rs149455805; hg19: chr20-22562607;