rs571330298

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr20-22581932-G-A
• chr20-22581932-G-C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_021784.5(FOXA2):​c.1310C>T​(p.Thr437Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,458,616 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FOXA2 NM_021784.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.38
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12363133).

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.1310C>T	p.Thr437Met	missense	Exon 2 of 2	NP_068556.2	B0ZTD4
	FOXA2	NM_153675.3		c.1292C>T	p.Thr431Met	missense	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.1310C>T	p.Thr437Met	missense	Exon 2 of 2	ENSP00000400341.3	Q9Y261-2
	FOXA2	ENST00000377115.4	TSL:1	c.1292C>T	p.Thr431Met	missense	Exon 3 of 3	ENSP00000366319.4	Q9Y261-1
	FOXA2	ENST00000938926.1		c.785C>T	p.Thr262Met	missense	Exon 2 of 2	ENSP00000608985.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 152210 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000799 AC: 2 AN: 250414 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1458616 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 724908

African (AFR) AF: 0.00 AC: 0 AN: 33410

American (AMR) AF: 0.00 AC: 0 AN: 44654

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26054

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39614

South Asian (SAS) AF: 0.00 AC: 0 AN: 86152

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53352

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1109370

Other (OTH) AF: 0.00 AC: 0 AN: 60254

GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 152328 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74484

African (AFR) AF: 0.00 AC: 0 AN: 41586

American (AMR) AF: 0.00 AC: 0 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5154

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2116

ExAC AF: 0.0000247 AC: 3

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Benign	0.41	T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.13
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	L
PhyloP100		1.4
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.043
Sift	Benign	0.099	T
Sift4G	Benign	0.11	T
Polyphen		0.35	B
Vest4		0.12
MutPred		0.45		Loss of methylation at K430 (P = 0.0295)
MVP		0.48
ClinPred		0.18	T
GERP RS		2.3
Varity_R		0.12
gMVP		0.31
Mutation Taster		=95/5	polymorphism

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: rs571330298; hg19: chr20-22562570; COSMIC: COSV101008577; COSMIC: COSV101008577;