NM_004497.3:c.97A>C

Variant names:

• chr19-45872102-A-C
• NM_004497.3:c.97A>C

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.97A>C​(p.Thr33Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000481 in 1,456,338 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: FOXA3 NM_004497.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.30
• 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=0.18375036).
• BS2: High AC in GnomAdExome4 at 7 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.97A>C	p.Thr33Pro	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.97A>C	p.Thr33Pro	missense	Exon 2 of 2	ENSP00000304004.1	P55318
	FOXA3	ENST00000594297.1	TSL:3	c.-3A>C		5_prime_UTR	Exon 2 of 2	ENSP00000470816.1	M0QZW5
	FOXA3	ENST00000876764.1		c.70-297A>C		intron	N/A	ENSP00000546823.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000481 AC: 7 AN: 1456338 Hom.: 0 Cov.: 31 AF XY: 0.00000414 AC XY: 3 AN XY: 724442

African (AFR) AF: 0.00 AC: 0 AN: 33294

American (AMR) AF: 0.00 AC: 0 AN: 43880

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25608

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 85510

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53234

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5730

European-Non Finnish (NFE) AF: 0.00000541 AC: 6 AN: 1109214

Other (OTH) AF: 0.0000166 AC: 1 AN: 60170

GnomAD4 genome Cov.: 32

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	0.070
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	23
DANN	Benign	0.97
DEOGEN2	Benign	0.25	T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.35	N
LIST_S2	Benign	0.52	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
PhyloP100		1.3
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.12
Sift	Uncertain	0.013	D
Sift4G	Benign	0.095	T
Polyphen		0.022	B
Vest4		0.11
MutPred		0.61		Gain of catalytic residue at P32 (P = 0.0186)
MVP		0.25
MPC		0.23
ClinPred		0.28	T
GERP RS		4.3
Varity_R		0.33
gMVP		0.49
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

hg19: chr19-46375360;