20-22581844-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_021784.5(FOXA2):c.*6C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00316 in 1,607,094 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0021 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0033 (8 hom.)
• Consequence: FOXA2 NM_021784.5 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -3.81

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 20-22581844-G-A is Benign according to our data. Variant chr20-22581844-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1338703.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 314 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FOXA2	NM_021784.5	c.*6C>T		3_prime_UTR_variant	2/2	ENST00000419308.7
FOXA2	NM_153675.3	c.*6C>T		3_prime_UTR_variant	3/3
FOXA2	XM_047440133.1	c.*6C>T		3_prime_UTR_variant	3/3
FOXA2	XM_047440134.1	c.*6C>T		3_prime_UTR_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FOXA2	ENST00000419308.7	c.*6C>T		3_prime_UTR_variant	2/2	1	NM_021784.5	P4
FOXA2	ENST00000377115.4	c.*6C>T		3_prime_UTR_variant	3/3	1		A1

Frequencies

GnomAD3 genomes AF: 0.00206 AC: 314 AN: 152126 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000628

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.00242

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00123

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00342

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00183 AC: 456 AN: 249286 Hom.: 2 AF XY: 0.00189 AC XY: 255 AN XY: 135276

Gnomad AFR exome AF: 0.000387

Gnomad AMR exome AF: 0.00101

Gnomad ASJ exome AF: 0.000402

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000787

Gnomad NFE exome AF: 0.00339

Gnomad OTH exome AF: 0.00198

GnomAD4 exome AF: 0.00328 AC: 4770 AN: 1454850 Hom.: 8 Cov.: 29 AF XY: 0.00311 AC XY: 2249 AN XY: 722346

Gnomad4 AFR exome AF: 0.000510

Gnomad4 AMR exome AF: 0.00117

Gnomad4 ASJ exome AF: 0.000385

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000930

Gnomad4 FIN exome AF: 0.00105

Gnomad4 NFE exome AF: 0.00405

Gnomad4 OTH exome AF: 0.00242

GnomAD4 genome AF: 0.00206 AC: 313 AN: 152244 Hom.: 1 Cov.: 32 AF XY: 0.00200 AC XY: 149 AN XY: 74428

Gnomad4 AFR AF: 0.000626

Gnomad4 AMR AF: 0.00242

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00123

Gnomad4 NFE AF: 0.00341

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00274 Hom.: 0

Bravo AF: 0.00214

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00273

EpiControl AF: 0.00332

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Aug 11, 2021

- -

FOXA2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 18, 2019

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

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jan 01, 2023

FOXA2: BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
Cadd	Benign	0.051
Dann	Benign	0.90

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: rs200967462; hg19: chr20-22562482;