rs1974

Positions:

• chr20-22581673-G-A
• chr20-22581673-G-C

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FOXA2	NM_021784.5	c.*177C>T		3_prime_UTR_variant	2/2	ENST00000419308.7	NP_068556.2
FOXA2	NM_153675.3	c.*177C>T		3_prime_UTR_variant	3/3		NP_710141.1
FOXA2	XM_047440133.1	c.*177C>T		3_prime_UTR_variant	3/3		XP_047296089.1
FOXA2	XM_047440134.1	c.*177C>T		3_prime_UTR_variant	2/2		XP_047296090.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FOXA2	ENST00000419308.7	c.*177C>T		3_prime_UTR_variant	2/2	1	NM_021784.5	ENSP00000400341	P4
FOXA2	ENST00000377115.4	c.*177C>T		3_prime_UTR_variant	3/3	1		ENSP00000366319	A1

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

Gnomad4 AFR exome AF: 0.435

Gnomad4 AMR exome AF: 0.0524

Gnomad4 ASJ exome AF: 0.0882

Gnomad4 EAS exome AF: 0.181

Gnomad4 SAS exome AF: 0.0428

Gnomad4 FIN exome AF: 0.0360

Gnomad4 NFE exome AF: 0.0443

Gnomad4 OTH exome AF: 0.0907

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

Gnomad4 AFR AF: 0.430

Gnomad4 AMR AF: 0.0759

Gnomad4 ASJ AF: 0.0890

Gnomad4 EAS AF: 0.156

Gnomad4 SAS AF: 0.0489

Gnomad4 FIN AF: 0.0333

Gnomad4 NFE AF: 0.0457

Gnomad4 OTH AF: 0.140

Alfa AF: 0.0890 Hom.: 316

Bravo AF: 0.175

Asia WGS AF: 0.149 AC: 518 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	8.2
DANN	Benign	0.81

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

Publications

LitVar

Other links and lift over

dbSNP: rs1974; hg19: chr20-22562311;