Genetic Variant KLF8:p.Ile108Leu (chrX-56265420-A-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_007250.5(KLF8):c.322A>T(p.Ile108Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000364 in 1,097,896 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I108V) has been classified as Benign.

Frequency

Genomes: not found (cov: 22)

Exomes 𝑓: 0.0000036 ( 0 hom. 0 hem. )

Consequence

KLF8
NM_007250.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.354

Publications

0 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.055877864).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007250.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KLF8	NM_007250.5	MANE Select	c.322A>T	p.Ile108Leu	missense	Exon 3 of 6	NP_009181.2	O95600-1
KLF8	NM_001324104.1		c.337A>T	p.Ile113Leu	missense	Exon 4 of 7	NP_001311033.1
KLF8	NM_001324102.1		c.322A>T	p.Ile108Leu	missense	Exon 4 of 7	NP_001311031.1	O95600-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KLF8	ENST00000468660.6	TSL:1 MANE Select	c.322A>T	p.Ile108Leu	missense	Exon 3 of 6	ENSP00000417303.1	O95600-1
KLF8	ENST00000640927.1	TSL:1	c.307A>T	p.Ile103Leu	missense	Exon 2 of 4	ENSP00000492126.1	O95600-4
KLF8	ENST00000358094.7	TSL:1	n.322A>T		non_coding_transcript_exon	Exon 3 of 7	ENSP00000431911.1	Q05BZ3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000364

AC:

AN:

1097896

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

363278

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26396

American (AMR)

AF:

0.00

AC:

AN:

35175

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19377

East Asian (EAS)

AF:

0.00

AC:

AN:

30201

South Asian (SAS)

AF:

0.00

AC:

AN:

54119

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40521

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4133

European-Non Finnish (NFE)

AF:

0.00000475

AC:

AN:

841884

Other (OTH)

AF:

0.00

AC:

AN:

46090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.413

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.92

CADD

Benign

0.16

(source)

DANN

Benign

0.83

DEOGEN2

Benign

0.095

FATHMM_MKL

Benign

0.079

LIST_S2

Benign

0.77

M_CAP

Benign

0.0019

MetaRNN

Benign

0.056

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.5

PhyloP100

-0.35

PrimateAI

Benign

0.44

PROVEAN

Benign

-1.2

REVEL

Benign

0.012

Sift

Benign

0.17

Sift4G

Benign

0.084

Polyphen

0.0010

Vest4

0.21

MutPred

0.19

Loss of loop (P = 0.0512)

MVP

0.44

MPC

0.098

ClinPred

0.15

GERP RS

-0.93

Varity_R

0.092

gMVP

0.093

Mutation Taster

=97/3

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