Genetic Variant KLF4:n.1435G>A (chr9-107487224-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000493306.1(KLF4):n.1435G>A variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.178 in 1,609,242 control chromosomes in the GnomAD database, including 27,499 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.15 ( 2217 hom., cov: 32)

Exomes 𝑓: 0.18 ( 25282 hom. )

Consequence

KLF4
ENST00000493306.1 non_coding_transcript_exon

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0790

Publications

22 publications found

Variant links:

Genes affected

KLF4 (HGNC:6348): (KLF transcription factor 4) This gene encodes a protein that belongs to the Kruppel family of transcription factors. The encoded zinc finger protein is required for normal development of the barrier function of skin. The encoded protein is thought to control the G1-to-S transition of the cell cycle following DNA damage by mediating the tumor suppressor gene p53. Mice lacking this gene have a normal appearance but lose weight rapidly, and die shortly after birth due to fluid evaporation resulting from compromised epidermal barrier function. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Sep 2015]

KLF4 Gene-Disease associations (from GenCC):

epidermal disease
Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics

KLF4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.269 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLF4	NM_004235.6 link	c.1100-32G>A		intron_variant	Intron 3 of 4	ENST00000374672.5	NP_004226.3	O43474-1
KLF4	NM_001314052.2 link	c.1170G>A	p.Gly390Gly	synonymous_variant	Exon 3 of 4		NP_001300981.1	O43474-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLF4	ENST00000374672.5 link	c.1100-32G>A		intron_variant	Intron 3 of 4	1	NM_004235.6	ENSP00000363804.4		O43474-1

Frequencies

GnomAD3 genomes

AF:

0.151

AC:

22965

AN:

151968

Hom.:

2218

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0364

Gnomad AMI

AF:

0.199

Gnomad AMR

AF:

0.167

Gnomad ASJ

AF:

0.248

Gnomad EAS

AF:

0.281

Gnomad SAS

AF:

0.0880

Gnomad FIN

AF:

0.272

Gnomad MID

AF:

0.184

Gnomad NFE

AF:

0.187

Gnomad OTH

AF:

0.171

GnomAD2 exomes

AF:

0.184

AC:

45312

AN:

246782

AF XY:

0.182

show subpopulations

Gnomad AFR exome

AF:

0.0327

Gnomad AMR exome

AF:

0.189

Gnomad ASJ exome

AF:

0.242

Gnomad EAS exome

AF:

0.288

Gnomad FIN exome

AF:

0.274

Gnomad NFE exome

AF:

0.190

Gnomad OTH exome

AF:

0.199

GnomAD4 exome

AF:

0.181

AC:

263912

AN:

1457156

Hom.:

25282

Cov.:

AF XY:

0.179

AC XY:

129511

AN XY:

724372

show subpopulations

African (AFR)

AF:

0.0277

AC:

926

AN:

33426

American (AMR)

AF:

0.187

AC:

8295

AN:

44448

Ashkenazi Jewish (ASJ)

AF:

0.241

AC:

6188

AN:

25662

East Asian (EAS)

AF:

0.274

AC:

10890

AN:

39674

South Asian (SAS)

AF:

0.0839

AC:

7173

AN:

85474

European-Finnish (FIN)

AF:

0.267

AC:

14181

AN:

53212

Middle Eastern (MID)

AF:

0.154

AC:

882

AN:

5742

European-Non Finnish (NFE)

AF:

0.184

AC:

204157

AN:

1109312

Other (OTH)

AF:

0.186

AC:

11220

AN:

60206

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

13364

26728

40092

53456

66820

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7098

14196

21294

28392

35490

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.151

AC:

22951

AN:

152086

Hom.:

2217

Cov.:

AF XY:

0.153

AC XY:

11385

AN XY:

74296

show subpopulations

African (AFR)

AF:

0.0362

AC:

1505

AN:

41540

American (AMR)

AF:

0.166

AC:

2544

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.248

AC:

859

AN:

3466

East Asian (EAS)

AF:

0.281

AC:

1441

AN:

5130

South Asian (SAS)

AF:

0.0870

AC:

419

AN:

4814

European-Finnish (FIN)

AF:

0.272

AC:

2866

AN:

10556

Middle Eastern (MID)

AF:

0.187

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.187

AC:

12721

AN:

67972

Other (OTH)

AF:

0.170

AC:

360

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

959

1918

2876

3835

4794

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

256

512

768

1024

1280

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.167

Hom.:

1818

Bravo

AF:

0.144

Asia WGS

AF:

0.201

AC:

696

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

2.1

(source)

DANN

Benign

0.62

PhyloP100

-0.079

BranchPoint Hunter

0.0

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over