chr20-22582134-G-T

Position:

• chr20-22582134-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_021784.5(FOXA2):​c.1108C>A​(p.Leu370Met) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: FOXA2 NM_021784.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.88

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3291215).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FOXA2	NM_021784.5	c.1108C>A	p.Leu370Met	missense_variant	2/2	ENST00000419308.7	NP_068556.2
FOXA2	NM_153675.3	c.1090C>A	p.Leu364Met	missense_variant	3/3		NP_710141.1
FOXA2	XM_047440133.1	c.1090C>A	p.Leu364Met	missense_variant	3/3		XP_047296089.1
FOXA2	XM_047440134.1	c.1000C>A	p.Leu334Met	missense_variant	2/2		XP_047296090.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FOXA2	ENST00000419308.7	c.1108C>A	p.Leu370Met	missense_variant	2/2	1	NM_021784.5	ENSP00000400341	P4
FOXA2	ENST00000377115.4	c.1090C>A	p.Leu364Met	missense_variant	3/3	1		ENSP00000366319	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 29, 2024

The c.1108C>A (p.L370M) alteration is located in exon 2 (coding exon 2) of the FOXA2 gene. This alteration results from a C to A substitution at nucleotide position 1108, causing the leucine (L) at amino acid position 370 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Uncertain	0.079	D
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.45	.;T
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.75	T;T
M_CAP	Pathogenic	0.34	D
MetaRNN	Benign	0.33	T;T
MetaSVM	Uncertain	0.41	D
MutationAssessor	Benign	1.6	.;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.77	.;N
REVEL	Uncertain	0.41
Sift	Benign	0.056	.;T
Sift4G	Benign	0.17	T;T
Polyphen		0.82	.;P
Vest4		0.31
MutPred		0.21		.;Loss of methylation at K365 (P = 0.0668);
MVP		0.68
ClinPred		0.84	D
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.18
gMVP		0.43

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr20-22562772;