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GeneBe

rs3810327

chr19-45872959-C-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_StrongBP6_ModerateBP7BA1

The NM_004497.3(FOXA3):c.954C>A(p.Pro318=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.091 in 1,613,926 control chromosomes in the GnomAD database, including 7,223 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.080 ( 545 hom., cov: 32)
Exomes 𝑓: 0.092 ( 6678 hom. )

Consequence

FOXA3
NM_004497.3 synonymous

Scores

2

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 2.90
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -15 ACMG points.

BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.47).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 19-45872959-C-A is Benign according to our data. Variant chr19-45872959-C-A is described in ClinVar as [Benign]. Clinvar id is 3059205.Status of the report is criteria_provided_single_submitter, 1 stars.
BP7
?
    BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=2.9 with no splicing effect.
BA1
?
    BA1 - Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0973 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
FOXA3NM_004497.3 linkuse as main transcriptc.954C>A p.Pro318= synonymous_variant 2/2 ENST00000302177.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
FOXA3ENST00000302177.3 linkuse as main transcriptc.954C>A p.Pro318= synonymous_variant 2/21 NM_004497.3 P1

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0798
AC:
12126
AN:
152014
Hom.:
546
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0338
Gnomad AMI
AF:
0.105
Gnomad AMR
AF:
0.0601
Gnomad ASJ
AF:
0.114
Gnomad EAS
AF:
0.0657
Gnomad SAS
AF:
0.0972
Gnomad FIN
AF:
0.147
Gnomad MID
AF:
0.111
Gnomad NFE
AF:
0.0992
Gnomad OTH
AF:
0.0853
GnomAD3 exomes
AF:
0.0898
AC:
22544
AN:
251014
Hom.:
1154
AF XY:
0.0932
AC XY:
12661
AN XY:
135792
show subpopulations
Gnomad AFR exome
AF:
0.0299
Gnomad AMR exome
AF:
0.0498
Gnomad ASJ exome
AF:
0.112
Gnomad EAS exome
AF:
0.0561
Gnomad SAS exome
AF:
0.0974
Gnomad FIN exome
AF:
0.149
Gnomad NFE exome
AF:
0.100
Gnomad OTH exome
AF:
0.100
GnomAD4 exome
AF:
0.0922
AC:
134813
AN:
1461794
Hom.:
6678
Cov.:
33
AF XY:
0.0929
AC XY:
67542
AN XY:
727188
show subpopulations
Gnomad4 AFR exome
AF:
0.0314
Gnomad4 AMR exome
AF:
0.0521
Gnomad4 ASJ exome
AF:
0.113
Gnomad4 EAS exome
AF:
0.0834
Gnomad4 SAS exome
AF:
0.0958
Gnomad4 FIN exome
AF:
0.148
Gnomad4 NFE exome
AF:
0.0927
Gnomad4 OTH exome
AF:
0.0885
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0797
AC:
12127
AN:
152132
Hom.:
545
Cov.:
32
AF XY:
0.0824
AC XY:
6130
AN XY:
74362
show subpopulations
Gnomad4 AFR
AF:
0.0337
Gnomad4 AMR
AF:
0.0599
Gnomad4 ASJ
AF:
0.114
Gnomad4 EAS
AF:
0.0659
Gnomad4 SAS
AF:
0.0970
Gnomad4 FIN
AF:
0.147
Gnomad4 NFE
AF:
0.0992
Gnomad4 OTH
AF:
0.0873
Alfa
AF:
0.0899
Hom.:
501
Bravo
AF:
0.0694
Asia WGS
AF:
0.0890
AC:
310
AN:
3478
EpiCase
AF:
0.0908
EpiControl
AF:
0.0933

ClinVar

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

Submissions by phenotype

FOXA3-related disorder Benign:1
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesFeb 22, 2019This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.47
Cadd
Benign
5.8
Dann
Benign
0.65

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: rs3810327; hg19: chr19-46376217; COSMIC: COSV56217169; COSMIC: COSV56217169; API