14-37591966-C-A

Variant names:

• chr14-37591966-C-A
• rs1024200279
• NM_004496.5:c.818G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004496.5(FOXA1):​c.818G>T​(p.Gly273Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000714 in 1,399,750 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G273E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: FOXA1 NM_004496.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.37
• Publications: 0 publications found

Genes affected

FOXA1 (HGNC:5021): (forkhead box A1) This gene encodes a member of the forkhead class of DNA-binding proteins. These hepatocyte nuclear factors are transcriptional activators for liver-specific transcripts 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. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30280623).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004496.5. 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
	FOXA1	NM_004496.5	MANE Select	c.818G>T	p.Gly273Val	missense	Exon 2 of 2	NP_004487.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXA1	ENST00000250448.5	TSL:1 MANE Select	c.818G>T	p.Gly273Val	missense	Exon 2 of 2	ENSP00000250448.3	P55317-1
	FOXA1	ENST00000545425.2	TSL:2	n.933G>T		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.14e-7 AC: 1 AN: 1399750 Hom.: 0 Cov.: 30 AF XY: 0.00000145 AC XY: 1 AN XY: 691736

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31244

American (AMR) AF: 0.00 AC: 0 AN: 35808

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22584

East Asian (EAS) AF: 0.00 AC: 0 AN: 38142

South Asian (SAS) AF: 0.00 AC: 0 AN: 76388

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48338

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4476

European-Non Finnish (NFE) AF: 9.22e-7 AC: 1 AN: 1085136

Other (OTH) AF: 0.00 AC: 0 AN: 57634

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	0.011	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.35	T
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.0076
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.48	T
M_CAP	Pathogenic	0.61	D
MetaRNN	Benign	0.30	T
MetaSVM	Uncertain	0.11	D
MutationAssessor	Benign	1.7	L
PhyloP100		2.4
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.29
Sift	Uncertain	0.019	D
Sift4G	Uncertain	0.054	T
Polyphen		0.51	P
Vest4		0.13
MutPred		0.33		Gain of catalytic residue at G277 (P = 0)
MVP		0.74
ClinPred		0.55	D
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.28
gMVP		0.49
Mutation Taster		=54/46	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: rs1024200279; hg19: chr14-38061171;