20-22581872-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM1 PP3 BS2

The NM_021784.5(FOXA2):c.1370G>A(p.Arg457Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000809 in 1,607,190 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: FOXA2 NM_021784.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.09

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 Likely_benign. Variant got -1 ACMG points.

• PM1: In a modified_residue Phosphoserine (size 0) in uniprot entity FOXA2_HUMAN
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.8
• BS2: High AC in GnomAd at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FOXA2	NM_021784.5	c.1370G>A	p.Arg457Gln	missense_variant	2/2	ENST00000419308.7
FOXA2	NM_153675.3	c.1352G>A	p.Arg451Gln	missense_variant	3/3
FOXA2	XM_047440133.1	c.1352G>A	p.Arg451Gln	missense_variant	3/3
FOXA2	XM_047440134.1	c.1262G>A	p.Arg421Gln	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FOXA2	ENST00000419308.7	c.1370G>A	p.Arg457Gln	missense_variant	2/2	1	NM_021784.5	P4
FOXA2	ENST00000377115.4	c.1352G>A	p.Arg451Gln	missense_variant	3/3	1		A1

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152132 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.0000160 AC: 4 AN: 249552 Hom.: 0 AF XY: 0.0000222 AC XY: 3 AN XY: 135296

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000869

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: 0.00000885

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000344 AC: 5 AN: 1454940 Hom.: 0 Cov.: 29 AF XY: 0.00000277 AC XY: 2 AN XY: 722176

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000449

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: 0.00000181

Gnomad4 OTH exome AF: 0.0000167

GnomAD4 genome AF: 0.0000525 AC: 8 AN: 152250 Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5 AN XY: 74420

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00142

Bravo AF: 0.0000756

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 08, 2022

ClinVar contains an entry for this variant (Variation ID: 1492754). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with FOXA2-related conditions. This variant is present in population databases (rs534577829, gnomAD 0.009%). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 457 of the FOXA2 protein (p.Arg457Gln). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Pathogenic	0.25
Cadd	Pathogenic	30
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.79	D
MetaRNN	Pathogenic	0.80	D;D
MetaSVM	Pathogenic	1.0	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.79	T
REVEL	Pathogenic	0.85
Sift4G	Uncertain	0.056	T;T
Polyphen		1.0	.;D
Vest4		0.90
MutPred		0.66		.;Loss of MoRF binding (P = 0.0763);
MVP		0.96
ClinPred		0.95	D
GERP RS		4.7
Varity_R		0.56
gMVP		0.58

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: rs534577829; hg19: chr20-22562510; COSMIC: COSV65796184; COSMIC: COSV65796184;