Genetic Variant FOXK1:p.Pro52Leu (chr7-4682463-C-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001037165.2(FOXK1):c.155C>T(p.Pro52Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000601 in 981,826 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000066 ( 0 hom. )

Consequence

FOXK1
NM_001037165.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0710

Variant links:

Genes affected

FOXK1 (HGNC:23480): (forkhead box K1) Enables 14-3-3 protein binding activity; DNA-binding transcription repressor activity, RNA polymerase II-specific; and transcription cis-regulatory region binding activity. Involved in several processes, including cellular glucose homeostasis; negative regulation of autophagy; and regulation of transcription, DNA-templated. Located in cytoplasm and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

FOXK1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.23671964).

BS2

High AC in GnomAdExome4 at 55 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXK1	NM_001037165.2 link	c.155C>T	p.Pro52Leu	missense_variant	Exon 1 of 9	ENST00000328914.5	NP_001032242.1	P85037-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOXK1	ENST00000328914.5 link	c.155C>T	p.Pro52Leu	missense_variant	Exon 1 of 9	2	NM_001037165.2	ENSP00000328720.4		P85037-1

Frequencies

GnomAD3 genomes

AF:

0.0000274

AC:

AN:

145924

Hom.:

Cov.:

show subpopulations

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:

0.0000608

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000658

AC:

AN:

835902

Hom.:

Cov.:

AF XY:

0.0000646

AC XY:

AN XY:

386762

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000694

Gnomad4 OTH exome

AF:

0.0000730

GnomAD4 genome

AF:

0.0000274

AC:

AN:

145924

Hom.:

Cov.:

AF XY:

0.0000423

AC XY:

AN XY:

70958

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000608

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000529

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 06, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.155C>T (p.P52L) alteration is located in exon 1 (coding exon 1) of the FOXK1 gene. This alteration results from a C to T substitution at nucleotide position 155, causing the proline (P) at amino acid position 52 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.046

BayesDel_noAF

Benign

-0.30

CADD

Benign

9.0

DANN

Uncertain

0.98

DEOGEN2

Benign

0.044

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.0015

LIST_S2

Benign

0.36

M_CAP

Pathogenic

0.59

MetaRNN

Benign

0.24

MetaSVM

Benign

-0.67

MutationAssessor

Benign

0.34

PrimateAI

Uncertain

0.63

PROVEAN

Benign

0.13

REVEL

Benign

0.24

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.031

Polyphen

0.0

Vest4

0.18

MutPred

0.37

Loss of glycosylation at P52 (P = 0.0022);

MVP

0.58

MPC

1.9

ClinPred

0.20

GERP RS

0.50

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.6

Varity_R

0.044

gMVP

0.18

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