Genetic Variant NM_001300.6:c.465C>G (chr10-3781852-G-C) – ACMG Classification: Likely_pathogenic (7 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 9P and 2B. PS1PM1PM2PP2BP4_Moderate

The NM_001300.6(KLF6):c.465C>G(p.Ser155Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,878 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

KLF6
NM_001300.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.46

Publications

0 publications found

Variant links:

Genes affected

KLF6 (HGNC:2235): (KLF transcription factor 6) This gene encodes a member of the Kruppel-like family of transcription factors. The zinc finger protein is a transcriptional activator, and functions as a tumor suppressor. Multiple transcript variants encoding different isoforms have been found for this gene, some of which are implicated in carcinogenesis. [provided by RefSeq, May 2009]

KLF6 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

PS1

Transcript NM_001300.6 (KLF6) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 7574

PM1

In a chain Krueppel-like factor 6 (size 282) in uniprot entity KLF6_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) in NM_001300.6

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 5 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: 1.8535 (below the threshold of 3.09). Trascript score misZ: 2.6969 (below the threshold of 3.09).

BP4

Computational evidence support a benign effect (MetaRNN=0.16149423).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLF6	NM_001300.6 link	c.465C>G	p.Ser155Arg	missense_variant	Exon 2 of 4	ENST00000497571.6	NP_001291.3	Q99612-1
KLF6	NM_001160124.2 link	c.465C>G	p.Ser155Arg	missense_variant	Exon 2 of 4		NP_001153596.1	Q99612D3GC14
KLF6	NM_001160125.2 link	c.465C>G	p.Ser155Arg	missense_variant	Exon 2 of 3		NP_001153597.1	Q99612-3
KLF6	NR_027653.2 link	n.660C>G		non_coding_transcript_exon_variant	Exon 2 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLF6	ENST00000497571.6 link	c.465C>G	p.Ser155Arg	missense_variant	Exon 2 of 4	1	NM_001300.6	ENSP00000419923.1		Q99612-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461878

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727242

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1112002

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.33

BayesDel_addAF

Benign

-0.097

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.44

T;.;.

Eigen

Benign

-0.14

Eigen_PC

Benign

-0.066

FATHMM_MKL

Benign

0.61

LIST_S2

Benign

0.77

T;D;D

M_CAP

Benign

0.017

MetaRNN

Benign

0.16

T;T;T

MetaSVM

Benign

-0.84

MutationAssessor

Uncertain

2.5

M;M;M

PhyloP100

2.5

PrimateAI

Benign

0.42

PROVEAN

Benign

-1.8

N;N;N

REVEL

Benign

0.031

Sift

Benign

0.038

D;D;D

Sift4G

Benign

0.32

T;T;T

Polyphen

0.11

B;.;P

Vest4

0.17

MutPred

0.27

Loss of phosphorylation at S155 (P = 0.0037);Loss of phosphorylation at S155 (P = 0.0037);Loss of phosphorylation at S155 (P = 0.0037);

MVP

0.43

MPC

1.1

ClinPred

0.73

GERP RS

2.3

Varity_R

0.14

gMVP

0.46

Mutation Taster

=13/87

disease causing

(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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over