Genetic Variant FOXA1:p.Val444Val (chr14-37591452-C-T) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_004496.5(FOXA1):c.1332G>A(p.Val444Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00487 in 1,614,194 control chromosomes in the GnomAD database, including 53 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0041 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0050 ( 51 hom. )

Consequence

FOXA1
NM_004496.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 2.12

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 made for transcript

Verdict is Benign. Variant got -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.46).

BP6

Variant 14-37591452-C-T is Benign according to our data. Variant chr14-37591452-C-T is described in ClinVar as [Benign]. Clinvar id is 790373.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=2.12 with no splicing effect.

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00495 (7242/1461858) while in subpopulation MID AF= 0.0335 (193/5768). AF 95% confidence interval is 0.0296. There are 51 homozygotes in gnomad4_exome. There are 3990 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck.

BS2

High AC in GnomAd4 at 620 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXA1	NM_004496.5 link	c.1332G>A	p.Val444Val	synonymous_variant	Exon 2 of 2	ENST00000250448.5	NP_004487.2	P55317-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOXA1	ENST00000250448.5 link	c.1332G>A	p.Val444Val	synonymous_variant	Exon 2 of 2	1	NM_004496.5	ENSP00000250448.3		P55317-1
FOXA1	ENST00000545425.2 link	n.1447G>A		non_coding_transcript_exon_variant	Exon 2 of 2	2

Frequencies

GnomAD3 genomes

AF:

0.00408

AC:

621

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000675

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00386

Gnomad ASJ

AF:

0.0213

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0133

Gnomad FIN

AF:

0.00792

Gnomad MID

AF:

0.0443

Gnomad NFE

AF:

0.00409

Gnomad OTH

AF:

0.00909

GnomAD3 exomes

AF:

0.00701

AC:

1763

AN:

251324

Hom.:

AF XY:

0.00786

AC XY:

1068

AN XY:

135888

show subpopulations

Gnomad AFR exome

AF:

0.000739

Gnomad AMR exome

AF:

0.00347

Gnomad ASJ exome

AF:

0.0200

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.0167

Gnomad FIN exome

AF:

0.00999

Gnomad NFE exome

AF:

0.00565

Gnomad OTH exome

AF:

0.00946

GnomAD4 exome

AF:

0.00495

AC:

7242

AN:

1461858

Hom.:

Cov.:

AF XY:

0.00549

AC XY:

3990

AN XY:

727230

show subpopulations

Gnomad4 AFR exome

AF:

0.00167

Gnomad4 AMR exome

AF:

0.00389

Gnomad4 ASJ exome

AF:

0.0201

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0165

Gnomad4 FIN exome

AF:

0.00878

Gnomad4 NFE exome

AF:

0.00354

Gnomad4 OTH exome

AF:

0.00780

GnomAD4 genome

AF:

0.00407

AC:

620

AN:

152336

Hom.:

Cov.:

AF XY:

0.00463

AC XY:

345

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.000697

Gnomad4 AMR

AF:

0.00385

Gnomad4 ASJ

AF:

0.0213

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0131

Gnomad4 FIN

AF:

0.00792

Gnomad4 NFE

AF:

0.00410

Gnomad4 OTH

AF:

0.00900

Alfa

AF:

0.00543

Hom.:

Bravo

AF:

0.00378

Asia WGS

AF:

0.00924

AC:

AN:

3478

EpiCase

AF:

0.00731

EpiControl

AF:

0.00688

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 13, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.46

CADD

Benign

9.5

DANN

Benign

0.97

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over