Genetic Variant NM_004496.5:c.247G>C (chr14-37592537-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_004496.5(FOXA1):c.247G>C(p.Ala83Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 13/22 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: 𝑓 0.0 ( 0 hom., cov: 34)

Failed GnomAD Quality Control

Consequence

FOXA1
NM_004496.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.56

Publications

51 publications found

Variant links:

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]

FOXA1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXA1	NM_004496.5 link	c.247G>C	p.Ala83Pro	missense_variant	Exon 2 of 2	ENST00000250448.5	NP_004487.2	P55317-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
FOXA1	ENST00000250448.5 link	c.247G>C	p.Ala83Pro	missense_variant	Exon 2 of 2	1	NM_004496.5	ENSP00000250448.3	P55317-1
FOXA1	ENST00000545425.2 link	n.362G>C		non_coding_transcript_exon_variant	Exon 2 of 2	2
FOXA1	ENST00000553751.1 link	n.*237G>C		non_coding_transcript_exon_variant	Exon 3 of 3	4		ENSP00000451704.1	G3V4B9
FOXA1	ENST00000553751.1 link	n.*237G>C		3_prime_UTR_variant	Exon 3 of 3	4		ENSP00000451704.1	G3V4B9

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

152034

Hom.:

Cov.:

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

GnomAD4 exome

Cov.:

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

152034

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74258

African (AFR)

AF:

0.00

AC:

AN:

41422

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5122

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67974

Other (OTH)

AF:

0.00

AC:

AN:

2090

Alfa

AF:

0.00

Hom.:

101787

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.51

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.38

Eigen

Benign

0.096

Eigen_PC

Benign

0.052

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.68

M_CAP

Benign

0.014

MetaRNN

Uncertain

0.53

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.2

PhyloP100

1.6

PrimateAI

Uncertain

0.70

PROVEAN

Benign

-0.99

REVEL

Benign

0.049

Sift

Benign

0.15

Sift4G

Benign

0.13

Polyphen

0.92

Vest4

0.12

MutPred

0.46

Gain of catalytic residue at M85 (P = 0);

MVP

0.39

ClinPred

0.41

GERP RS

3.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.19

gMVP

0.71

Mutation Taster

=55/45

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over