NM_004514.4:c.418G>A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_004514.4(FOXK2):c.418G>A(p.Val140Met) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000397 in 1,259,948 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000018 ( 0 hom. )

Consequence

FOXK2
NM_004514.4 missense, splice_region

Scores

Splicing: ADA: 0.01615

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.33

Publications

0 publications found

Variant links:

Genes affected

FOXK2 (HGNC:6036): (forkhead box K2) The protein encoded by this gene contains a fork head DNA binding domain. This protein can bind to the purine-rich motifs of the HIV long terminal repeat (LTR), and to the similar purine-rich motif in the interleukin 2 (IL2) promoter. It may be involved in the regulation of viral and cellular promoter elements. [provided by RefSeq, Jul 2008]

FOXK2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.28855294).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXK2	NM_004514.4 link	c.418G>A	p.Val140Met	missense_variant, splice_region_variant	Exon 1 of 9	ENST00000335255.10	NP_004505.2	Q01167-1
FOXK2	XM_047435919.1 link	c.418G>A	p.Val140Met	missense_variant, splice_region_variant	Exon 1 of 9		XP_047291875.1
FOXK2	XM_047435920.1 link	c.418G>A	p.Val140Met	missense_variant, splice_region_variant	Exon 1 of 5		XP_047291876.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
FOXK2	ENST00000335255.10 link	c.418G>A	p.Val140Met	missense_variant, splice_region_variant	Exon 1 of 9	1	NM_004514.4	ENSP00000335677.5	Q01167-1
FOXK2	ENST00000473637.6 link	n.418G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 1 of 10	1		ENSP00000436108.2	Q01167-2
FOXK2	ENST00000527313.6 link	n.330G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 1 of 3	3
FOXK2	ENST00000570585.1 link	n.13G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 1 of 4	3

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

151956

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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

AF:

0.00000181

AC:

AN:

1107992

Hom.:

Cov.:

AF XY:

0.00000380

AC XY:

AN XY:

526694

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

22468

American (AMR)

AF:

0.000124

AC:

AN:

8074

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

14158

East Asian (EAS)

AF:

0.00

AC:

AN:

25826

South Asian (SAS)

AF:

0.00

AC:

AN:

24682

European-Finnish (FIN)

AF:

0.00

AC:

AN:

36520

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3068

European-Non Finnish (NFE)

AF:

0.00000108

AC:

AN:

929168

Other (OTH)

AF:

0.00

AC:

AN:

44028

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.400

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000197

AC:

AN:

151956

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74234

show subpopulations

African (AFR)

AF:

0.0000483

AC:

AN:

41430

American (AMR)

AF:

0.0000655

AC:

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10550

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67928

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000340

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 31, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.418G>A (p.V140M) alteration is located in exon 1 (coding exon 1) of the FOXK2 gene. This alteration results from a G to A substitution at nucleotide position 418, causing the valine (V) at amino acid position 140 to be replaced by a methionine (M). 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

0.15

BayesDel_addAF

Benign

-0.042

BayesDel_noAF

Benign

-0.30

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.076

Eigen

Benign

-0.083

Eigen_PC

Benign

0.016

FATHMM_MKL

Benign

0.29

LIST_S2

Uncertain

0.89

M_CAP

Pathogenic

0.98

MetaRNN

Benign

0.29

MetaSVM

Uncertain

0.39

MutationAssessor

Benign

0.27

PhyloP100

1.3

PrimateAI

Pathogenic

0.91

PROVEAN

Benign

-0.37

REVEL

Benign

0.29

Sift

Benign

0.16

Sift4G

Benign

0.12

Polyphen

0.13

Vest4

0.053

MutPred

0.71

Loss of phosphorylation at T142 (P = 0.0898);

MVP

0.35

MPC

1.2

ClinPred

0.39

GERP RS

3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.15

gMVP

0.36

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.016

dbscSNV1_RF

Benign

0.21

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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NM_004514.4:c.418G>A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over