Variant X-56265483-A-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_007250.5(KLF8):c.385A>C(p.Met129Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000744 in 1,210,349 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 0.0000073 ( 0 hom. 5 hem. )

Consequence

KLF8
NM_007250.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.839

Variant links:

Genes affected

KLF8 (HGNC:6351): (KLF transcription factor 8) This gene encodes a protein which is a member of the Sp/KLF family of transcription factors. Members of this family contain a C-terminal DNA-binding domain with three Kruppel-like zinc fingers. The encoded protein is thought to play an important role in the regulation of epithelial to mesenchymal transition, a process which occurs normally during development but also during metastasis. A pseudogene has been identified on chromosome 16. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2009]

KLF8 links:

KLF8 (HGNC:):

KLF8 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.03696403).

BS2

High Hemizygotes in GnomAdExome4 at 5 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLF8	NM_007250.5 linkuse as main transcript	c.385A>C	p.Met129Leu	missense_variant	3/6	ENST00000468660.6	NP_009181.2	O95600-1A0A024R9X4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLF8	ENST00000468660.6 linkuse as main transcript	c.385A>C	p.Met129Leu	missense_variant	3/6	1	NM_007250.5	ENSP00000417303.1		O95600-1

Frequencies

GnomAD3 genomes

AF:

0.00000891

AC:

AN:

112195

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34339

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:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000109

AC:

AN:

183324

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

67806

show subpopulations

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000244

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000728

AC:

AN:

1098154

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

363520

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:

0.00000831

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000891

AC:

AN:

112195

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34339

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:

0.0000188

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 15, 2023

The c.385A>C (p.M129L) alteration is located in exon 3 (coding exon 3) of the KLF8 gene. This alteration results from a A to C substitution at nucleotide position 385, causing the methionine (M) at amino acid position 129 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

0.21

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-1.1

CADD

Benign

1.0

DANN

Benign

0.41

DEOGEN2

Benign

0.060

.;T;.

FATHMM_MKL

Benign

0.012

LIST_S2

Benign

0.54

T;T;T

M_CAP

Benign

0.0011

MetaRNN

Benign

0.037

T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

-0.14

N;N;.

PrimateAI

Benign

0.30

PROVEAN

Benign

0.18

N;N;.

REVEL

Benign

0.010

Sift

Benign

0.64

T;T;.

Sift4G

Benign

0.49

T;T;.

Polyphen

0.0

.;B;.

Vest4

0.070

MutPred

0.26

Gain of phosphorylation at T131 (P = 0.101);Gain of phosphorylation at T131 (P = 0.101);.;

MVP

0.45

MPC

0.086

ClinPred

0.030

GERP RS

0.094

Varity_R

0.079

gMVP

0.13

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