19-45872844-C-G

Variant names:

• chr19-45872844-C-G
• rs760139463
• NM_004497.3:c.839C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004497.3(FOXA3):​c.839C>G​(p.Thr280Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. T280I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FOXA3 NM_004497.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.486
• Publications: 0 publications found

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]

ACMG classification

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=0.1607342).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004497.3. 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
	FOXA3	NM_004497.3	MANE Select	c.839C>G	p.Thr280Arg	missense	Exon 2 of 2	NP_004488.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXA3	ENST00000302177.3	TSL:1 MANE Select	c.839C>G	p.Thr280Arg	missense	Exon 2 of 2	ENSP00000304004.1	P55318
	FOXA3	ENST00000876764.1		c.515C>G	p.Thr172Arg	missense	Exon 2 of 2	ENSP00000546823.1
	FOXA3	ENST00000876765.1		c.512C>G	p.Thr171Arg	missense	Exon 2 of 2	ENSP00000546824.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.0060	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	18
DANN	Benign	0.95
DEOGEN2	Benign	0.38	T
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.59	T
M_CAP	Uncertain	0.090	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	0.55	N
PhyloP100		0.49
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.18
Sift	Benign	0.55	T
Sift4G	Benign	0.62	T
Polyphen		0.0	B
Vest4		0.34
MutPred		0.29		Loss of phosphorylation at T280 (P = 0.0017)
MVP		0.94
MPC		0.20
ClinPred		0.050	T
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.088
gMVP		0.66
Mutation Taster		=91/9	polymorphism

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

Other links and lift over

dbSNP: rs760139463; hg19: chr19-46376102;