Genetic Variant FOXA2:p.Thr437Arg (chr20-22581932-G-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_021784.5(FOXA2):c.1310C>G(p.Thr437Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,458,616 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T437M) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

FOXA2
NM_021784.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.38

Publications

2 publications found

Variant links:

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]

FOXA2 Gene-Disease associations (from GenCC):

combined pituitary hormone deficiencies, genetic form
Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, ClinGen

FOXA2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.12661779).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021784.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXA2	NM_021784.5	MANE Select	c.1310C>G	p.Thr437Arg	missense	Exon 2 of 2	NP_068556.2	B0ZTD4
	FOXA2	NM_153675.3		c.1292C>G	p.Thr431Arg	missense	Exon 3 of 3	NP_710141.1	Q9Y261-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FOXA2	ENST00000419308.7	TSL:1 MANE Select	c.1310C>G	p.Thr437Arg	missense	Exon 2 of 2	ENSP00000400341.3	Q9Y261-2
FOXA2	ENST00000377115.4	TSL:1	c.1292C>G	p.Thr431Arg	missense	Exon 3 of 3	ENSP00000366319.4	Q9Y261-1
FOXA2	ENST00000938926.1		c.785C>G	p.Thr262Arg	missense	Exon 2 of 2	ENSP00000608985.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000399

AC:

AN:

250414

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000206

AC:

AN:

1458616

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

724908

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33410

American (AMR)

AF:

0.00

AC:

AN:

44654

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26054

East Asian (EAS)

AF:

0.00

AC:

AN:

39614

South Asian (SAS)

AF:

0.00

AC:

AN:

86152

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53352

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1109370

Other (OTH)

AF:

0.00

AC:

AN:

60254

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.39

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.40

Eigen

Benign

-0.48

Eigen_PC

Benign

-0.31

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.74

M_CAP

Benign

0.015

MetaRNN

Benign

0.13

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.55

PhyloP100

1.4

PrimateAI

Benign

0.43

PROVEAN

Benign

-0.91

REVEL

Benign

0.063

Sift

Benign

0.54

Sift4G

Benign

0.55

Polyphen

0.014

Vest4

0.15

MutPred

0.53

Loss of glycosylation at T431 (P = 0.0401)

MVP

0.39

ClinPred

0.085

GERP RS

2.3

Varity_R

0.38

gMVP

0.37

Mutation Taster

=93/7

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over