chr19-45872721-C-T

Variant names:

• chr19-45872721-C-T
• rs749657388
• NM_004497.3:c.716C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

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. 15/22 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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.23
• 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: Likely_benign. The variant received -6 ACMG points.

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

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.716C>T	p.Ser239Leu	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.716C>T	p.Ser239Leu	missense	Exon 2 of 2	ENSP00000304004.1	P55318
	FOXA3	ENST00000876764.1		c.392C>T	p.Ser131Leu	missense	Exon 2 of 2	ENSP00000546823.1
	FOXA3	ENST00000876765.1		c.389C>T	p.Ser130Leu	missense	Exon 2 of 2	ENSP00000546824.1

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152006 Hom.: 0 Cov.: 32

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

GnomAD2 exomes AF: 0.0000225 AC: 5 AN: 221906 AF XY: 0.0000246

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 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

African (AFR) AF: 0.0000300 AC: 1 AN: 33316

American (AMR) AF: 0.0000459 AC: 2 AN: 43584

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25840

East Asian (EAS) AF: 0.00 AC: 0 AN: 39316

South Asian (SAS) AF: 0.00 AC: 0 AN: 85494

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50696

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5704

European-Non Finnish (NFE) AF: 0.000235 AC: 260 AN: 1107618

Other (OTH) AF: 0.000134 AC: 8 AN: 59906

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152006 Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5 AN XY: 74252

African (AFR) AF: 0.0000725 AC: 3 AN: 41368

American (AMR) AF: 0.00 AC: 0 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000736 AC: 5 AN: 67966

Other (OTH) AF: 0.00 AC: 0 AN: 2090

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

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		1.2
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
Mutation Taster		=98/2	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: rs749657388; hg19: chr19-46375979;