chr20-22581673-G-A

Variant names:

• chr20-22581673-G-A
• rs1974
• NM_021784.5:c.*177C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_021784.5(FOXA2):​c.*177C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0908 in 607,368 control chromosomes in the GnomAD database, including 6,507 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.16 (4159 hom., cov: 32)
  • Exomes 𝑓: 0.068 (2348 hom.)
• Consequence: FOXA2 NM_021784.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.949
• Publications: 7 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.425 is higher than 0.05.

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.*177C>T		3_prime_UTR	Exon 2 of 2	NP_068556.2	B0ZTD4
	FOXA2	NM_153675.3		c.*177C>T		3_prime_UTR	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.*177C>T		3_prime_UTR	Exon 2 of 2	ENSP00000400341.3	Q9Y261-2
	FOXA2	ENST00000377115.4	TSL:1	c.*177C>T		3_prime_UTR	Exon 3 of 3	ENSP00000366319.4	Q9Y261-1
	FOXA2	ENST00000938926.1		c.*177C>T		3_prime_UTR	Exon 2 of 2	ENSP00000608985.1

Frequencies

GnomAD3 genomes AF: 0.158 AC: 24023 AN: 151642 Hom.: 4121 Cov.: 32

Gnomad AFR AF: 0.429

Gnomad AMI AF: 0.131

Gnomad AMR AF: 0.0762

Gnomad ASJ AF: 0.0890

Gnomad EAS AF: 0.155

Gnomad SAS AF: 0.0492

Gnomad FIN AF: 0.0333

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0456

Gnomad OTH AF: 0.139

GnomAD4 exome AF: 0.0681 AC: 31022 AN: 455608 Hom.: 2348 Cov.: 5 AF XY: 0.0658 AC XY: 15674 AN XY: 238318

African (AFR) AF: 0.435 AC: 5467 AN: 12562

American (AMR) AF: 0.0524 AC: 990 AN: 18884

Ashkenazi Jewish (ASJ) AF: 0.0882 AC: 1183 AN: 13412

East Asian (EAS) AF: 0.181 AC: 5616 AN: 31010

South Asian (SAS) AF: 0.0428 AC: 1820 AN: 42498

European-Finnish (FIN) AF: 0.0360 AC: 1264 AN: 35142

Middle Eastern (MID) AF: 0.0901 AC: 173 AN: 1920

European-Non Finnish (NFE) AF: 0.0443 AC: 12149 AN: 274150

Other (OTH) AF: 0.0907 AC: 2360 AN: 26030

GnomAD4 genome AF: 0.159 AC: 24119 AN: 151760 Hom.: 4159 Cov.: 32 AF XY: 0.155 AC XY: 11501 AN XY: 74188

African (AFR) AF: 0.430 AC: 17728 AN: 41214

American (AMR) AF: 0.0759 AC: 1160 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.0890 AC: 308 AN: 3462

East Asian (EAS) AF: 0.156 AC: 802 AN: 5148

South Asian (SAS) AF: 0.0489 AC: 235 AN: 4810

European-Finnish (FIN) AF: 0.0333 AC: 352 AN: 10558

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.0457 AC: 3105 AN: 67984

Other (OTH) AF: 0.140 AC: 296 AN: 2108

Alfa AF: 0.0922 Hom.: 2628

Bravo AF: 0.175

Asia WGS AF: 0.149 AC: 518 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	8.2
DANN	Benign	0.81
PhyloP100		0.95
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: rs1974; hg19: chr20-22562311;