Genetic Variant KLF5:p.Pro25Leu (chr13-73059401-C-T) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_001730.5(KLF5):c.74C>T(p.Pro25Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000343 in 1,398,324 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

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

Exomes 𝑓: 0.000036 ( 0 hom. )

Consequence

KLF5
NM_001730.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.00

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.30184972).

BS2

High AC in GnomAdExome4 at 45 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLF5	NM_001730.5 link	c.74C>T	p.Pro25Leu	missense_variant	Exon 1 of 4	ENST00000377687.6	NP_001721.2	Q13887-1Q5T6X2
KLF5	NM_001286818.2 link	c.-12-2460C>T		intron_variant	Intron 1 of 3		NP_001273747.1	Q13887-4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
KLF5	ENST00000377687.6 link	c.74C>T	p.Pro25Leu	missense_variant	Exon 1 of 4	1	NM_001730.5	ENSP00000366915.4	Q13887-1
KLF5	ENST00000539231.5 link	c.-12-2460C>T		intron_variant	Intron 1 of 3	1		ENSP00000440407.1	Q13887-4
KLF5	ENST00000477333.5 link	n.184-2460C>T		intron_variant	Intron 1 of 1	2

Frequencies

GnomAD3 genomes

AF:

0.0000198

AC:

AN:

151308

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:

0.0000445

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000249

AC:

AN:

40110

Hom.:

AF XY:

0.0000428

AC XY:

AN XY:

23342

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000123

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS 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:

0.0000361

AC:

AN:

1247016

Hom.:

Cov.:

AF XY:

0.0000425

AC XY:

AN XY:

611324

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000521

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:

0.0000426

Gnomad4 OTH exome

AF:

0.0000197

GnomAD4 genome

AF:

0.0000198

AC:

AN:

151308

Hom.:

Cov.:

AF XY:

0.0000271

AC XY:

AN XY:

73836

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:

0.0000445

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000416

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 30, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.74C>T (p.P25L) alteration is located in exon 1 (coding exon 1) of the KLF5 gene. This alteration results from a C to T substitution at nucleotide position 74, causing the proline (P) at amino acid position 25 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

0.30

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.38

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.18

Eigen

Uncertain

0.36

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.83

M_CAP

Pathogenic

0.66

MetaRNN

Benign

0.30

MetaSVM

Benign

-1.0

MutationAssessor

Benign

2.0

PrimateAI

Pathogenic

0.94

PROVEAN

Benign

-0.58

REVEL

Benign

0.12

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.021

Polyphen

0.99

Vest4

0.23

MutPred

0.32

Gain of loop (P = 0.0312);

MVP

0.31

MPC

0.77

ClinPred

0.56

GERP RS

4.4

Varity_R

0.24

gMVP

0.30

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