chr14-37591930-C-T

Variant names:

• chr14-37591930-C-T
• rs1369165182
• NM_004496.5:c.854G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_004496.5(FOXA1):​c.854G>A​(p.Ser285Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000127 in 1,340,794 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: FOXA1 NM_004496.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.21
• Publications: 2 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.12609082).
• BS2: High AC in GnomAdExome4 at 17 AD gene.

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.854G>A	p.Ser285Asn	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.854G>A	p.Ser285Asn	missense	Exon 2 of 2	ENSP00000250448.3	P55317-1
	FOXA1	ENST00000545425.2	TSL:2	n.969G>A		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000404 AC: 4 AN: 99132 AF XY: 0.0000381

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000104

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000127 AC: 17 AN: 1340794 Hom.: 0 Cov.: 29 AF XY: 0.0000107 AC XY: 7 AN XY: 657148

African (AFR) AF: 0.00 AC: 0 AN: 29432

American (AMR) AF: 0.00 AC: 0 AN: 27602

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20404

East Asian (EAS) AF: 0.00 AC: 0 AN: 35752

South Asian (SAS) AF: 0.00 AC: 0 AN: 68892

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41860

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4172

European-Non Finnish (NFE) AF: 0.0000161 AC: 17 AN: 1057380

Other (OTH) AF: 0.00 AC: 0 AN: 55300

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

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	0.095
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	14
DANN	Benign	0.96
DEOGEN2	Benign	0.30	T
Eigen	Benign	-0.96
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.22	T
M_CAP	Pathogenic	0.56	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	0.69	N
PhyloP100		1.2
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-0.64	N
REVEL	Benign	0.12
Sift	Benign	0.20	T
Sift4G	Benign	0.51	T
Polyphen		0.023	B
Vest4		0.10
MutPred		0.29		Gain of catalytic residue at S280 (P = 0)
MVP		0.47
ClinPred		0.039	T
GERP RS		1.9
Varity_R		0.11
gMVP		0.17
Mutation Taster		=96/4	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: rs1369165182; hg19: chr14-38061135; COSMIC: COSV99032153;