20-22581932-G-C

Variant names:

• chr20-22581932-G-C
• rs571330298
• NM_021784.5:c.1310C>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_021784.5(FOXA2):​c.1310C>G​(p.Thr437Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,458,616 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign 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: 0.0000021 (0 hom.)
• Consequence: FOXA2 NM_021784.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.38

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12661779).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXA2	NM_021784.5	c.1310C>G	p.Thr437Arg	missense_variant	Exon 2 of 2	ENST00000419308.7	NP_068556.2
FOXA2	NM_153675.3	c.1292C>G	p.Thr431Arg	missense_variant	Exon 3 of 3		NP_710141.1
FOXA2	XM_047440133.1	c.1292C>G	p.Thr431Arg	missense_variant	Exon 3 of 3		XP_047296089.1
FOXA2	XM_047440134.1	c.1202C>G	p.Thr401Arg	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.1310C>G	p.Thr437Arg	missense_variant	Exon 2 of 2	1	NM_021784.5	ENSP00000400341.3
FOXA2	ENST00000377115.4	c.1292C>G	p.Thr431Arg	missense_variant	Exon 3 of 3	1		ENSP00000366319.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250414 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135412

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1458616 Hom.: 0 Cov.: 30 AF XY: 0.00000276 AC XY: 2 AN XY: 724908

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	20
DANN	Benign	0.92
DEOGEN2	Benign	0.40	.;T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.31
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.74	T;T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.13	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	.;N
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.91	.;N
REVEL	Benign	0.063
Sift	Benign	0.54	.;T
Sift4G	Benign	0.55	T;T
Polyphen		0.014	.;B
Vest4		0.15
MutPred		0.53		.;Loss of glycosylation at T431 (P = 0.0401);
MVP		0.39
ClinPred		0.085	T
GERP RS		2.3
Varity_R		0.38
gMVP		0.37

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: rs571330298; hg19: chr20-22562570;