rs1196201504

Variant names:

• chr19-45872829-C-T
• rs1196201504
• NM_004497.3:c.824C>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.824C>T​(p.Ser275Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000093 in 1,612,970 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: FOXA3 NM_004497.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.03
• 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=0.23527732).
• BS2: High AC in GnomAdExome4 at 13 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.824C>T	p.Ser275Leu	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.824C>T	p.Ser275Leu	missense	Exon 2 of 2	ENSP00000304004.1	P55318
	FOXA3	ENST00000876764.1		c.500C>T	p.Ser167Leu	missense	Exon 2 of 2	ENSP00000546823.1
	FOXA3	ENST00000876765.1		c.497C>T	p.Ser166Leu	missense	Exon 2 of 2	ENSP00000546824.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152196 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000890 AC: 13 AN: 1460774 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 726722

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52322

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000989 AC: 11 AN: 1112004

Other (OTH) AF: 0.0000166 AC: 1 AN: 60382

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152196 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74348

African (AFR) AF: 0.0000483 AC: 2 AN: 41446

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

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	0.10
BayesDel_addAF	Uncertain	0.031	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.38	T
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.28
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.71	T
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.24	T
MetaSVM	Uncertain	-0.094	T
MutationAssessor	Benign	0.69	N
PhyloP100		1.0
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.19
Sift	Benign	0.16	T
Sift4G	Benign	0.21	T
Polyphen		0.0010	B
Vest4		0.32
MutPred		0.31		Loss of glycosylation at S275 (P = 0.0189)
MVP		0.91
MPC		0.18
ClinPred		0.10	T
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.11
gMVP		0.55
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: rs1196201504; hg19: chr19-46376087; COSMIC: COSV108834690; COSMIC: COSV108834690;