rs1212275

Positions:

• chr20-22582036-T-A
• chr20-22582036-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000419308.7(FOXA2):​c.1206A>T​(p.Gln402His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. Q402Q) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FOXA2 ENST00000419308.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0760

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_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.041766822).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FOXA2	NM_021784.5	c.1206A>T	p.Gln402His	missense_variant	2/2	ENST00000419308.7	NP_068556.2
FOXA2	NM_153675.3	c.1188A>T	p.Gln396His	missense_variant	3/3		NP_710141.1
FOXA2	XM_047440133.1	c.1188A>T	p.Gln396His	missense_variant	3/3		XP_047296089.1
FOXA2	XM_047440134.1	c.1098A>T	p.Gln366His	missense_variant	2/2		XP_047296090.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FOXA2	ENST00000419308.7	c.1206A>T	p.Gln402His	missense_variant	2/2	1	NM_021784.5	ENSP00000400341	P4
FOXA2	ENST00000377115.4	c.1188A>T	p.Gln396His	missense_variant	3/3	1		ENSP00000366319	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 91

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	14
DANN	Benign	0.65
DEOGEN2	Benign	0.26	.;T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.68	T;T
M_CAP	Pathogenic	0.29	D
MetaRNN	Benign	0.042	T;T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	-1.1	.;N
MutationTaster	Benign	0.90	N;N;N
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.080	.;N
REVEL	Benign	0.24
Sift	Benign	0.22	.;T
Sift4G	Benign	0.36	T;T
Polyphen		0.0	.;B
Vest4		0.17
MutPred		0.33		.;Gain of glycosylation at S391 (P = 0.2128);
MVP		0.33
ClinPred		0.11	T
GERP RS		0.84
Varity_R		0.051
gMVP		0.39

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: rs1212275; hg19: chr20-22562674;