chr19-45872721-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_004497.3(FOXA3):​c.716C>T​(p.Ser239Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000174 in 1,603,480 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00019 ( 0 hom. )

Consequence

FOXA3
NM_004497.3 missense

Scores

5
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.23
Variant links:
Genes affected
FOXA3 (HGNC:5023): (forkhead box A3) This gene encodes a member of the forkhead class of DNA-binding proteins. These hepatocyte nuclear factors are transcriptional activators for liver-specific transcripts 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. The crystal structure of a similar protein in rat has been resolved. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.14297783).
BS2
High AC in GnomAd4 at 8 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
FOXA3NM_004497.3 linkuse as main transcriptc.716C>T p.Ser239Leu missense_variant 2/2 ENST00000302177.3 NP_004488.2 P55318A0A024R0R3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
FOXA3ENST00000302177.3 linkuse as main transcriptc.716C>T p.Ser239Leu missense_variant 2/21 NM_004497.3 ENSP00000304004.1 P55318

Frequencies

GnomAD3 genomes
AF:
0.0000526
AC:
8
AN:
152006
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000725
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.0000736
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000225
AC:
5
AN:
221906
Hom.:
0
AF XY:
0.0000246
AC XY:
3
AN XY:
122156
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000307
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:
0.0000407
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000187
AC:
271
AN:
1451474
Hom.:
0
Cov.:
32
AF XY:
0.000182
AC XY:
131
AN XY:
721478
show subpopulations
Gnomad4 AFR exome
AF:
0.0000300
Gnomad4 AMR exome
AF:
0.0000459
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:
0.000235
Gnomad4 OTH exome
AF:
0.000134
GnomAD4 genome
AF:
0.0000526
AC:
8
AN:
152006
Hom.:
0
Cov.:
32
AF XY:
0.0000673
AC XY:
5
AN XY:
74252
show subpopulations
Gnomad4 AFR
AF:
0.0000725
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000736
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000566
Hom.:
0
Bravo
AF:
0.0000453
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.000519
AC:
2
ExAC
AF:
0.0000498
AC:
6

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsSep 30, 2021The c.716C>T (p.S239L) alteration is located in exon 2 (coding exon 2) of the FOXA3 gene. This alteration results from a C to T substitution at nucleotide position 716, causing the serine (S) at amino acid position 239 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.099
BayesDel_addAF
Benign
-0.20
T
BayesDel_noAF
Benign
-0.35
CADD
Benign
17
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.67
D
Eigen
Benign
-0.93
Eigen_PC
Benign
-0.95
FATHMM_MKL
Benign
0.17
N
LIST_S2
Benign
0.51
T
M_CAP
Benign
0.077
D
MetaRNN
Benign
0.14
T
MetaSVM
Benign
-0.44
T
MutationAssessor
Benign
0.34
N
PrimateAI
Benign
0.47
T
PROVEAN
Uncertain
-3.0
D
REVEL
Benign
0.16
Sift
Uncertain
0.015
D
Sift4G
Uncertain
0.0070
D
Polyphen
0.0
B
Vest4
0.098
MutPred
0.29
Loss of glycosylation at S239 (P = 4e-04);
MVP
0.77
MPC
0.17
ClinPred
0.061
T
GERP RS
1.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.074
gMVP
0.49

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs749657388; hg19: chr19-46375979; API