Genetic Variant ENST00000469435.1:c.782G>A (chr10-3781535-C-T) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 3P and 8B. PM1PP2BP4_StrongBS2

The ENST00000469435.1(KLF6):c.782G>A(p.Arg261Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000142 in 1,560,402 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as not provided (no stars).

Frequency

Genomes: 𝑓 0.00073 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000078 ( 0 hom. )

Consequence

KLF6
ENST00000469435.1 missense

Scores

Clinical Significance

not provided no classification provided O:1

Conservation

PhyloP100: 0.528

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

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 ENST00000469435.1

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: 1.628 (below the threshold of 3.09).

BP4

Computational evidence support a benign effect (MetaRNN=0.003863871).

BS2

High AC in GnomAd4 at 112 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
KLF6	NM_001300.6 link	c.676+106G>A	intron_variant	Intron 2 of 3	ENST00000497571.6	NP_001291.3	Q99612-1
KLF6	NM_001160124.2 link	c.550+232G>A	intron_variant	Intron 2 of 3		NP_001153596.1	Q99612D3GC14
KLF6	NM_001160125.2 link	c.676+106G>A	intron_variant	Intron 2 of 2		NP_001153597.1	Q99612-3
KLF6	NR_027653.2 link	n.717+260G>A	intron_variant	Intron 2 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
KLF6	ENST00000469435.1 link	c.782G>A	p.Arg261Lys	missense_variant	Exon 2 of 2	1		ENSP00000419079.1	Q99612-2
KLF6	ENST00000497571.6 link	c.676+106G>A		intron_variant	Intron 2 of 3	1	NM_001300.6	ENSP00000419923.1	Q99612-1
KLF6	ENST00000542957.1 link	c.676+106G>A		intron_variant	Intron 2 of 2	5		ENSP00000445301.1	Q99612-3
KLF6	ENST00000173785.4 link	n.257+260G>A		intron_variant	Intron 1 of 2	2

Frequencies

GnomAD3 genomes

AF:

0.000736

AC:

112

AN:

152274

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00258

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

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:

0.00

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000133

AC:

AN:

165522

AF XY:

0.000124

show subpopulations

Gnomad AFR exome

AF:

0.00205

Gnomad AMR exome

AF:

0.000158

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:

0.000214

GnomAD4 exome

AF:

0.0000781

AC:

110

AN:

1408010

Hom.:

Cov.:

AF XY:

0.0000719

AC XY:

AN XY:

695660

show subpopulations

African (AFR)

AF:

0.00264

AC:

AN:

31874

American (AMR)

AF:

0.000138

AC:

AN:

36228

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25282

East Asian (EAS)

AF:

0.00

AC:

AN:

36148

South Asian (SAS)

AF:

0.00

AC:

AN:

80758

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49382

Middle Eastern (MID)

AF:

0.000351

AC:

AN:

5704

European-Non Finnish (NFE)

AF:

0.00000461

AC:

AN:

1084126

Other (OTH)

AF:

0.000239

AC:

AN:

58508

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000735

AC:

112

AN:

152392

Hom.:

Cov.:

AF XY:

0.000751

AC XY:

AN XY:

74526

show subpopulations

African (AFR)

AF:

0.00257

AC:

107

AN:

41602

American (AMR)

AF:

0.000261

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68038

Other (OTH)

AF:

0.000473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000511

Hom.:

Bravo

AF:

0.000910

ExAC

AF:

0.000184

AC:

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

LINK: link

Submissions by phenotype

not specified

Other:1

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.65

CADD

Benign

7.7

(source)

DANN

Benign

0.93

Eigen

Benign

-0.87

Eigen_PC

Benign

-0.91

FATHMM_MKL

Benign

0.024

LIST_S2

Benign

0.16

M_CAP

Benign

0.0058

MetaRNN

Benign

0.0039

MetaSVM

Benign

-1.0

PhyloP100

0.53

PROVEAN

Benign

0.23

REVEL

Benign

0.012

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.034

Vest4

0.075

MVP

0.21

ClinPred

0.074

GERP RS

2.7

Mutation Taster

=99/1

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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ENST00000469435.1:c.782G>A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over