20-22581872-C-G

Variant names:

• chr20-22581872-C-G
• rs534577829
• NM_021784.5:c.1370G>C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_021784.5(FOXA2):​c.1370G>C​(p.Arg457Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000275 in 1,454,940 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: FOXA2 NM_021784.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.09

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a modified_residue Phosphoserine (size 0) in uniprot entity FOXA2_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.928

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXA2	NM_021784.5	c.1370G>C	p.Arg457Pro	missense_variant	Exon 2 of 2	ENST00000419308.7	NP_068556.2
FOXA2	NM_153675.3	c.1352G>C	p.Arg451Pro	missense_variant	Exon 3 of 3		NP_710141.1
FOXA2	XM_047440133.1	c.1352G>C	p.Arg451Pro	missense_variant	Exon 3 of 3		XP_047296089.1
FOXA2	XM_047440134.1	c.1262G>C	p.Arg421Pro	missense_variant	Exon 2 of 2		XP_047296090.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOXA2	ENST00000419308.7	c.1370G>C	p.Arg457Pro	missense_variant	Exon 2 of 2	1	NM_021784.5	ENSP00000400341.3
FOXA2	ENST00000377115.4	c.1352G>C	p.Arg451Pro	missense_variant	Exon 3 of 3	1		ENSP00000366319.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249552 Hom.: 0 AF XY: 0.00000739 AC XY: 1 AN XY: 135296

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 SAS exome AF: 0.0000328

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000275 AC: 4 AN: 1454940 Hom.: 0 Cov.: 29 AF XY: 0.00000415 AC XY: 3 AN XY: 722176

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000465

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	.;D
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.97	D;D
M_CAP	Pathogenic	0.81	D
MetaRNN	Pathogenic	0.93	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.6	.;M
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-4.0	.;D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	.;D
Sift4G	Uncertain	0.0060	D;D
Polyphen		1.0	.;D
Vest4		0.95
MutPred		0.69		.;Gain of disorder (P = 0.0278);
MVP		0.94
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.84
gMVP		0.66

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: rs534577829; hg19: chr20-22562510;