Genetic Variant KLF5:p.Pro70Leu (chr13-73059536-C-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001730.5(KLF5):c.209C>T(p.Pro70Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000244 in 1,186,272 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P70S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

KLF5
NM_001730.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0510

Publications

0 publications found

Variant links:

Genes affected

KLF5 (HGNC:6349): (KLF transcription factor 5) This gene encodes a member of the Kruppel-like factor subfamily of zinc finger proteins. The encoded protein is a transcriptional activator that binds directly to a specific recognition motif in the promoters of target genes. This protein acts downstream of multiple different signaling pathways and is regulated by post-translational modification. It may participate in both promoting and suppressing cell proliferation. Expression of this gene may be changed in a variety of different cancers and in cardiovascular disease. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2013]

KLF5 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.05731207).

BS2

High AC in GnomAd4 at 17 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001730.5. 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
	KLF5	NM_001730.5	MANE Select	c.209C>T	p.Pro70Leu	missense	Exon 1 of 4	NP_001721.2
	KLF5	NM_001286818.2		c.-12-2325C>T		intron	N/A	NP_001273747.1	Q13887-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KLF5	ENST00000377687.6	TSL:1 MANE Select	c.209C>T	p.Pro70Leu	missense	Exon 1 of 4	ENSP00000366915.4	Q13887-1
KLF5	ENST00000539231.5	TSL:1	c.-12-2325C>T		intron	N/A	ENSP00000440407.1	Q13887-4
KLF5	ENST00000851191.1		c.209C>T	p.Pro70Leu	missense	Exon 1 of 3	ENSP00000521250.1

Frequencies

GnomAD3 genomes

AF:

0.000113

AC:

AN:

150528

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000662

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00160

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00

AC:

AN:

432

AF XY:

0.00

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000116

AC:

AN:

1035636

Hom.:

Cov.:

AF XY:

0.00000810

AC XY:

AN XY:

493628

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

20768

American (AMR)

AF:

0.00

AC:

AN:

6616

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

11566

East Asian (EAS)

AF:

0.00

AC:

AN:

20674

South Asian (SAS)

AF:

0.00

AC:

AN:

20246

European-Finnish (FIN)

AF:

0.000600

AC:

AN:

18344

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2624

European-Non Finnish (NFE)

AF:

0.00000112

AC:

AN:

895196

Other (OTH)

AF:

0.00

AC:

AN:

39602

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.658

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000113

AC:

AN:

150636

Hom.:

Cov.:

AF XY:

0.000163

AC XY:

AN XY:

73550

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41346

American (AMR)

AF:

0.0000661

AC:

AN:

15134

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3452

East Asian (EAS)

AF:

0.00

AC:

AN:

5122

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00160

AC:

AN:

10018

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67438

Other (OTH)

AF:

0.00

AC:

AN:

2098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00

Hom.:

Bravo

AF:

0.0000113

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.63

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.14

Eigen

Benign

-0.75

Eigen_PC

Benign

-0.64

FATHMM_MKL

Benign

0.41

LIST_S2

Benign

0.62

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.057

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.34

PhyloP100

0.051

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

0.38

REVEL

Benign

0.024

Sift

Benign

0.077

Sift4G

Benign

0.13

Polyphen

0.076

Vest4

0.086

MutPred

0.21

Loss of glycosylation at P70 (P = 0.0243)

MVP

0.18

MPC

0.23

ClinPred

0.22

GERP RS

2.4

Varity_R

0.062

gMVP

0.15

Mutation Taster

=86/14

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over