20-22582238-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_021784.5(FOXA2):c.1004C>G(p.Ala335Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000755 in 1,323,746 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.6e-7 (0 hom.)
• Consequence: FOXA2 NM_021784.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.80

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1949867).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FOXA2	NM_021784.5	c.1004C>G	p.Ala335Gly	missense_variant	2/2	ENST00000419308.7
FOXA2	NM_153675.3	c.986C>G	p.Ala329Gly	missense_variant	3/3
FOXA2	XM_047440133.1	c.986C>G	p.Ala329Gly	missense_variant	3/3
FOXA2	XM_047440134.1	c.896C>G	p.Ala299Gly	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FOXA2	ENST00000419308.7	c.1004C>G	p.Ala335Gly	missense_variant	2/2	1	NM_021784.5	P4
FOXA2	ENST00000377115.4	c.986C>G	p.Ala329Gly	missense_variant	3/3	1		A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.55e-7 AC: 1 AN: 1323746 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 649120

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 9.51e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Jan 13, 2024

This sequence change replaces alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 335 of the FOXA2 protein (p.Ala335Gly). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with FOXA2-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The glycine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.091	T
BayesDel_noAF	Benign	-0.37
Cadd	Benign	15
Dann	Benign	0.48
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.79
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.44	T;T
M_CAP	Pathogenic	0.58	D
MetaRNN	Benign	0.19	T;T
MetaSVM	Benign	-0.54	T
MutationTaster	Benign	0.98	D;D;D
PrimateAI	Uncertain	0.77	T
REVEL	Benign	0.14
Sift4G	Benign	0.71	T;T
Polyphen		0.0010	.;B
Vest4		0.085
MutPred		0.25		.;Gain of catalytic residue at A329 (P = 0.116);
MVP		0.40
ClinPred		0.028	T
GERP RS		3.2
Varity_R		0.099
gMVP		0.37

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr20-22562876;