20-22582156-C-A

Variant names:

• chr20-22582156-C-A
• rs777713858
• NM_021784.5:c.1086G>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP7 BS2

The NM_021784.5(FOXA2):​c.1086G>T​(p.Pro362Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000849 in 1,413,378 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. P362P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000085 (0 hom.)
• Consequence: FOXA2 NM_021784.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -7.77
• Publications: 2 publications found

Genes affected

FOXA2 (HGNC:5022): (forkhead box A2) This gene encodes a member of the forkhead class of DNA-binding proteins. These hepatocyte nuclear factors are transcriptional activators for liver-specific genes 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. This gene has been linked to sporadic cases of maturity-onset diabetes of the young. Transcript variants encoding different isoforms have been identified for this gene. [provided by RefSeq, Oct 2008]

FOXA2 Gene-Disease associations (from GenCC):

• combined pituitary hormone deficiencies, genetic form

  Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, ClinGen

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP7: Synonymous conserved (PhyloP=-7.77 with no splicing effect.
• BS2: High AC in GnomAdExome4 at 12 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021784.5. 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
	FOXA2	NM_021784.5	MANE Select	c.1086G>T	p.Pro362Pro	synonymous	Exon 2 of 2	NP_068556.2	B0ZTD4
	FOXA2	NM_153675.3		c.1068G>T	p.Pro356Pro	synonymous	Exon 3 of 3	NP_710141.1	Q9Y261-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXA2	ENST00000419308.7	TSL:1 MANE Select	c.1086G>T	p.Pro362Pro	synonymous	Exon 2 of 2	ENSP00000400341.3	Q9Y261-2
	FOXA2	ENST00000377115.4	TSL:1	c.1068G>T	p.Pro356Pro	synonymous	Exon 3 of 3	ENSP00000366319.4	Q9Y261-1
	FOXA2	ENST00000938926.1		c.561G>T	p.Pro187Pro	synonymous	Exon 2 of 2	ENSP00000608985.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000590 AC: 1 AN: 169516 AF XY: 0.0000111

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000147

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000849 AC: 12 AN: 1413378 Hom.: 0 Cov.: 35 AF XY: 0.0000100 AC XY: 7 AN XY: 698686

African (AFR) AF: 0.00 AC: 0 AN: 32308

American (AMR) AF: 0.00 AC: 0 AN: 36718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25374

East Asian (EAS) AF: 0.00 AC: 0 AN: 36576

South Asian (SAS) AF: 0.00 AC: 0 AN: 81382

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50186

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

European-Non Finnish (NFE) AF: 0.0000110 AC: 12 AN: 1086578

Other (OTH) AF: 0.00 AC: 0 AN: 58552

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.079
DANN	Benign	0.86
PhyloP100		-7.8

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: rs777713858; hg19: chr20-22562794;