chr19-45872350-C-T

Variant names:

• chr19-45872350-C-T
• rs144459600
• NM_004497.3:c.345C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_004497.3(FOXA3):​c.345C>T​(p.His115His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.01 in 1,614,180 control chromosomes in the GnomAD database, including 113 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0069 (3 hom., cov: 32)
  • Exomes 𝑓: 0.010 (110 hom.)
• Consequence: FOXA3 NM_004497.3 synonymous
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -1.71
• Publications: 3 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=-0.52).
• BP6: Variant 19-45872350-C-T is Benign according to our data. Variant chr19-45872350-C-T is described in ClinVar as Benign. ClinVar VariationId is 3041583.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=-1.71 with no splicing effect.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.0103 (15111/1461844) while in subpopulation MID AF = 0.0182 (105/5768). AF 95% confidence interval is 0.0154. There are 110 homozygotes in GnomAdExome4. There are 7409 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1045 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.345C>T	p.His115His	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.345C>T	p.His115His	synonymous	Exon 2 of 2	ENSP00000304004.1	P55318
	FOXA3	ENST00000594297.1	TSL:3	c.246C>T	p.His82His	synonymous	Exon 2 of 2	ENSP00000470816.1	M0QZW5
	FOXA3	ENST00000876764.1		c.70-49C>T		intron	N/A	ENSP00000546823.1

Frequencies

GnomAD3 genomes AF: 0.00685 AC: 1042 AN: 152218 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00210

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.00582

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00393

Gnomad FIN AF: 0.00932

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0104

Gnomad OTH AF: 0.00765

GnomAD2 exomes AF: 0.00795 AC: 1996 AN: 251134 AF XY: 0.00820

Gnomad AFR exome AF: 0.00160

Gnomad AMR exome AF: 0.00654

Gnomad ASJ exome AF: 0.00328

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00893

Gnomad NFE exome AF: 0.0115

Gnomad OTH exome AF: 0.00847

GnomAD4 exome AF: 0.0103 AC: 15111 AN: 1461844 Hom.: 110 Cov.: 32 AF XY: 0.0102 AC XY: 7409 AN XY: 727220

African (AFR) AF: 0.00143 AC: 48 AN: 33480

American (AMR) AF: 0.00662 AC: 296 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00276 AC: 72 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00620 AC: 535 AN: 86258

European-Finnish (FIN) AF: 0.00861 AC: 460 AN: 53396

Middle Eastern (MID) AF: 0.0182 AC: 105 AN: 5768

European-Non Finnish (NFE) AF: 0.0117 AC: 13059 AN: 1111994

Other (OTH) AF: 0.00886 AC: 535 AN: 60392

GnomAD4 genome AF: 0.00686 AC: 1045 AN: 152336 Hom.: 3 Cov.: 32 AF XY: 0.00663 AC XY: 494 AN XY: 74484

African (AFR) AF: 0.00209 AC: 87 AN: 41576

American (AMR) AF: 0.00581 AC: 89 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3472

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

South Asian (SAS) AF: 0.00455 AC: 22 AN: 4834

European-Finnish (FIN) AF: 0.00932 AC: 99 AN: 10622

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0104 AC: 709 AN: 68012

Other (OTH) AF: 0.00757 AC: 16 AN: 2114

Alfa AF: 0.00884 Hom.: 2

Bravo AF: 0.00658

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0113

EpiControl AF: 0.0100

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	-0.52
CADD	Benign	2.4
DANN	Benign	0.91
PhyloP100		-1.7
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs144459600; hg19: chr19-46375608;