rs1800847

chr20-22582933-G-Achr20-22582933-G-Cchr20-22582933-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_021784.5(FOXA2):c.309C>T(p.Ala103=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0502 in 1,528,470 control chromosomes in the GnomAD database, including 3,153 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.080 (733 hom., cov: 33)
  • Exomes 𝑓: 0.047 (2420 hom.)
• Consequence: FOXA2 NM_021784.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.643

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 20-22582933-G-A is Benign according to our data. Variant chr20-22582933-G-A is described in ClinVar as [Benign]. Clinvar id is 1569424.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.643 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.157 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FOXA2	NM_021784.5	c.309C>T	p.Ala103=	synonymous_variant	2/2	ENST00000419308.7
FOXA2	NM_153675.3	c.291C>T	p.Ala97=	synonymous_variant	3/3
FOXA2	XM_047440133.1	c.291C>T	p.Ala97=	synonymous_variant	3/3
FOXA2	XM_047440134.1	c.201C>T	p.Ala67=	synonymous_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FOXA2	ENST00000419308.7	c.309C>T	p.Ala103=	synonymous_variant	2/2	1	NM_021784.5	P4
FOXA2	ENST00000377115.4	c.291C>T	p.Ala97=	synonymous_variant	3/3	1		A1

Frequencies

GnomAD3 genomes AF: 0.0799 AC: 12133 AN: 151914 Hom.: 727 Cov.: 33

Gnomad AFR AF: 0.160

Gnomad AMI AF: 0.127

Gnomad AMR AF: 0.0453

Gnomad ASJ AF: 0.0908

Gnomad EAS AF: 0.157

Gnomad SAS AF: 0.0870

Gnomad FIN AF: 0.0233

Gnomad MID AF: 0.0350

Gnomad NFE AF: 0.0401

Gnomad OTH AF: 0.0786

GnomAD3 exomes AF: 0.0712 AC: 9347 AN: 131320 Hom.: 517 AF XY: 0.0710 AC XY: 5194 AN XY: 73146

Gnomad AFR exome AF: 0.225

Gnomad AMR exome AF: 0.0342

Gnomad ASJ exome AF: 0.0989

Gnomad EAS exome AF: 0.180

Gnomad SAS exome AF: 0.0971

Gnomad FIN exome AF: 0.0258

Gnomad NFE exome AF: 0.0468

Gnomad OTH exome AF: 0.0658

GnomAD4 exome AF: 0.0469 AC: 64568 AN: 1376450 Hom.: 2420 Cov.: 35 AF XY: 0.0481 AC XY: 32709 AN XY: 680274

Gnomad4 AFR exome AF: 0.174

Gnomad4 AMR exome AF: 0.0329

Gnomad4 ASJ exome AF: 0.0913

Gnomad4 EAS exome AF: 0.183

Gnomad4 SAS exome AF: 0.0838

Gnomad4 FIN exome AF: 0.0274

Gnomad4 NFE exome AF: 0.0355

Gnomad4 OTH exome AF: 0.0639

GnomAD4 genome AF: 0.0800 AC: 12161 AN: 152020 Hom.: 733 Cov.: 33 AF XY: 0.0792 AC XY: 5888 AN XY: 74322

Gnomad4 AFR AF: 0.161

Gnomad4 AMR AF: 0.0452

Gnomad4 ASJ AF: 0.0908

Gnomad4 EAS AF: 0.157

Gnomad4 SAS AF: 0.0869

Gnomad4 FIN AF: 0.0233

Gnomad4 NFE AF: 0.0401

Gnomad4 OTH AF: 0.0802

Alfa AF: 0.0361 Hom.: 53

Bravo AF: 0.0849

Asia WGS AF: 0.148 AC: 508 AN: 3452

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

Sep 17, 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

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
Cadd	Benign	5.1
Dann	Benign	0.94
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

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: rs1800847; hg19: chr20-22563571;