14-37592537-C-T

Variant names:

• chr14-37592537-C-T
• rs7144658
• NM_004496.5:c.247G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004496.5(FOXA1):​c.247G>A​(p.Ala83Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.596 in 1,613,240 control chromosomes in the GnomAD database, including 290,586 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 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 0.56 (24820 hom., cov: 34)
  • Exomes 𝑓: 0.60 (265766 hom.)
• Consequence: FOXA1 NM_004496.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.56
• Publications: 51 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=8.9052753E-7).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.834 is higher than 0.05.

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.247G>A	p.Ala83Thr	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.247G>A	p.Ala83Thr	missense	Exon 2 of 2	ENSP00000250448.3	P55317-1
	FOXA1	ENST00000545425.2	TSL:2	n.362G>A		non_coding_transcript_exon	Exon 2 of 2
	FOXA1	ENST00000553751.1	TSL:4	n.*237G>A		non_coding_transcript_exon	Exon 3 of 3	ENSP00000451704.1	G3V4B9

Frequencies

GnomAD3 genomes AF: 0.562 AC: 85433 AN: 152004 Hom.: 24802 Cov.: 34

Gnomad AFR AF: 0.423

Gnomad AMI AF: 0.728

Gnomad AMR AF: 0.644

Gnomad ASJ AF: 0.537

Gnomad EAS AF: 0.856

Gnomad SAS AF: 0.565

Gnomad FIN AF: 0.628

Gnomad MID AF: 0.547

Gnomad NFE AF: 0.595

Gnomad OTH AF: 0.562

GnomAD2 exomes AF: 0.617 AC: 152220 AN: 246808 AF XY: 0.610

Gnomad AFR exome AF: 0.422

Gnomad AMR exome AF: 0.713

Gnomad ASJ exome AF: 0.549

Gnomad EAS exome AF: 0.865

Gnomad FIN exome AF: 0.631

Gnomad NFE exome AF: 0.593

Gnomad OTH exome AF: 0.605

GnomAD4 exome AF: 0.600 AC: 876657 AN: 1461120 Hom.: 265766 Cov.: 89 AF XY: 0.598 AC XY: 434684 AN XY: 726786

African (AFR) AF: 0.418 AC: 13981 AN: 33466

American (AMR) AF: 0.707 AC: 31604 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.549 AC: 14352 AN: 26124

East Asian (EAS) AF: 0.867 AC: 34395 AN: 39686

South Asian (SAS) AF: 0.561 AC: 48415 AN: 86242

European-Finnish (FIN) AF: 0.628 AC: 33365 AN: 53108

Middle Eastern (MID) AF: 0.542 AC: 3128 AN: 5766

European-Non Finnish (NFE) AF: 0.595 AC: 661562 AN: 1111656

Other (OTH) AF: 0.594 AC: 35855 AN: 60368

GnomAD4 genome AF: 0.562 AC: 85484 AN: 152120 Hom.: 24820 Cov.: 34 AF XY: 0.566 AC XY: 42103 AN XY: 74368

African (AFR) AF: 0.423 AC: 17567 AN: 41530

American (AMR) AF: 0.644 AC: 9858 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.537 AC: 1866 AN: 3472

East Asian (EAS) AF: 0.855 AC: 4371 AN: 5110

South Asian (SAS) AF: 0.564 AC: 2720 AN: 4822

European-Finnish (FIN) AF: 0.628 AC: 6659 AN: 10608

Middle Eastern (MID) AF: 0.561 AC: 165 AN: 294

European-Non Finnish (NFE) AF: 0.595 AC: 40418 AN: 67958

Other (OTH) AF: 0.567 AC: 1196 AN: 2108

Alfa AF: 0.587 Hom.: 101787

Bravo AF: 0.564

TwinsUK AF: 0.581 AC: 2156

ALSPAC AF: 0.591 AC: 2277

ESP6500AA AF: 0.441 AC: 1897

ESP6500EA AF: 0.589 AC: 4870

ExAC AF: 0.604 AC: 72959

Asia WGS AF: 0.693 AC: 2407 AN: 3474

EpiCase AF: 0.575

EpiControl AF: 0.580

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	16
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.38
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.62	T
MetaRNN	Benign	8.9e-7	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.64	N
PhyloP100		1.6
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.23	N
REVEL	Benign	0.030
Sift	Uncertain	0.014	D
Sift4G	Benign	0.40	T
Polyphen		0.0090	B
Vest4		0.021
ClinPred		0.0096	T
GERP RS		3.0
Varity_R		0.072
gMVP		0.60
Mutation Taster		=89/11	polymorphism (auto)

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: rs7144658; hg19: chr14-38061742; COSMIC: COSV51649579; COSMIC: COSV51649579;