rs3810327

Variant names:

• chr19-45872959-C-A
• rs3810327
• NM_004497.3:c.954C>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BA1

The NM_004497.3(FOXA3):​c.954C>A​(p.Pro318Pro) 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 (no stars).

• Frequency:
  • Genomes: 𝑓 0.080 (545 hom., cov: 32)
  • Exomes 𝑓: 0.092 (6678 hom.)
• Consequence: FOXA3 NM_004497.3 synonymous
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 2.90
• Publications: 11 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 19-45872959-C-A is Benign according to our data. Variant chr19-45872959-C-A is described in ClinVar as Benign. ClinVar VariationId is 3059205.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=2.9 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0973 is higher than 0.05.

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.954C>A	p.Pro318Pro	synonymous	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.954C>A	p.Pro318Pro	synonymous	Exon 2 of 2	ENSP00000304004.1	P55318
	FOXA3	ENST00000876764.1		c.630C>A	p.Pro210Pro	synonymous	Exon 2 of 2	ENSP00000546823.1
	FOXA3	ENST00000876765.1		c.627C>A	p.Pro209Pro	synonymous	Exon 2 of 2	ENSP00000546824.1

Frequencies

GnomAD3 genomes AF: 0.0798 AC: 12126 AN: 152014 Hom.: 546 Cov.: 32

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

GnomAD2 exomes AF: 0.0898 AC: 22544 AN: 251014 AF XY: 0.0932

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 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

African (AFR) AF: 0.0314 AC: 1051 AN: 33480

American (AMR) AF: 0.0521 AC: 2331 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.113 AC: 2956 AN: 26136

East Asian (EAS) AF: 0.0834 AC: 3310 AN: 39698

South Asian (SAS) AF: 0.0958 AC: 8263 AN: 86246

European-Finnish (FIN) AF: 0.148 AC: 7923 AN: 53404

Middle Eastern (MID) AF: 0.0915 AC: 528 AN: 5768

European-Non Finnish (NFE) AF: 0.0927 AC: 103104 AN: 1111962

Other (OTH) AF: 0.0885 AC: 5347 AN: 60386

GnomAD4 genome AF: 0.0797 AC: 12127 AN: 152132 Hom.: 545 Cov.: 32 AF XY: 0.0824 AC XY: 6130 AN XY: 74362

African (AFR) AF: 0.0337 AC: 1401 AN: 41524

American (AMR) AF: 0.0599 AC: 917 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.114 AC: 394 AN: 3470

East Asian (EAS) AF: 0.0659 AC: 341 AN: 5176

South Asian (SAS) AF: 0.0970 AC: 466 AN: 4802

European-Finnish (FIN) AF: 0.147 AC: 1550 AN: 10562

Middle Eastern (MID) AF: 0.105 AC: 31 AN: 294

European-Non Finnish (NFE) AF: 0.0992 AC: 6747 AN: 67986

Other (OTH) AF: 0.0873 AC: 184 AN: 2108

Alfa AF: 0.0890 Hom.: 555

Bravo AF: 0.0694

Asia WGS AF: 0.0890 AC: 310 AN: 3478

EpiCase AF: 0.0908

EpiControl AF: 0.0933

ClinVar

ClinVar submissions

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	FOXA3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	5.8
DANN	Benign	0.65
PhyloP100		2.9
Mutation Taster		=100/0	polymorphism (auto)

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