rs35927125

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_003597.5(KLF11):c.185A>G(p.Gln62Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.108 in 1,614,130 control chromosomes in the GnomAD database, including 10,225 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.088 ( 712 hom., cov: 33)

Exomes 𝑓: 0.11 ( 9513 hom. )

Consequence

KLF11
NM_003597.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1B:5

Conservation

PhyloP100: 2.09

Variant links:

Genes affected

KLF11 (HGNC:11811): (KLF transcription factor 11) The protein encoded by this gene is a zinc finger transcription factor that binds to SP1-like sequences in epsilon- and gamma-globin gene promoters. This binding inhibits cell growth and causes apoptosis. Defects in this gene are a cause of maturity-onset diabetes of the young type 7 (MODY7). Three transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Apr 2010]

KLF11 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0014551878).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.117 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
KLF11	NM_003597.5 linkuse as main transcript	c.185A>G	p.Gln62Arg	missense_variant	2/4	ENST00000305883.6
KLF11	NM_001177716.2 linkuse as main transcript	c.134A>G	p.Gln45Arg	missense_variant	2/4
KLF11	NM_001177718.2 linkuse as main transcript	c.134A>G	p.Gln45Arg	missense_variant	2/4
KLF11	XM_047446025.1 linkuse as main transcript	c.134A>G	p.Gln45Arg	missense_variant	2/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KLF11	ENST00000305883.6 linkuse as main transcript	c.185A>G	p.Gln62Arg	missense_variant	2/4	1	NM_003597.5	A2	O14901-1

Frequencies

GnomAD3 genomes

AF:

0.0877

AC:

13342

AN:

152154

Hom.:

712

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0466

Gnomad AMI

AF:

0.228

Gnomad AMR

AF:

0.0888

Gnomad ASJ

AF:

0.137

Gnomad EAS

AF:

0.00115

Gnomad SAS

AF:

0.0628

Gnomad FIN

AF:

0.0684

Gnomad MID

AF:

0.108

Gnomad NFE

AF:

0.119

Gnomad OTH

AF:

0.0999

GnomAD3 exomes

AF:

0.0926

AC:

23274

AN:

251402

Hom.:

1309

AF XY:

0.0954

AC XY:

12964

AN XY:

135880

show subpopulations

Gnomad AFR exome

AF:

0.0459

Gnomad AMR exome

AF:

0.0728

Gnomad ASJ exome

AF:

0.145

Gnomad EAS exome

AF:

0.000653

Gnomad SAS exome

AF:

0.0725

Gnomad FIN exome

AF:

0.0773

Gnomad NFE exome

AF:

0.123

Gnomad OTH exome

AF:

0.109

GnomAD4 exome

AF:

0.110

AC:

160944

AN:

1461858

Hom.:

9513

Cov.:

AF XY:

0.109

AC XY:

79569

AN XY:

727230

show subpopulations

Gnomad4 AFR exome

AF:

0.0445

Gnomad4 AMR exome

AF:

0.0737

Gnomad4 ASJ exome

AF:

0.144

Gnomad4 EAS exome

AF:

0.000252

Gnomad4 SAS exome

AF:

0.0731

Gnomad4 FIN exome

AF:

0.0785

Gnomad4 NFE exome

AF:

0.121

Gnomad4 OTH exome

AF:

0.102

GnomAD4 genome

AF:

0.0876

AC:

13345

AN:

152272

Hom.:

712

Cov.:

AF XY:

0.0849

AC XY:

6321

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.0466

Gnomad4 AMR

AF:

0.0887

Gnomad4 ASJ

AF:

0.137

Gnomad4 EAS

AF:

0.00116

Gnomad4 SAS

AF:

0.0624

Gnomad4 FIN

AF:

0.0684

Gnomad4 NFE

AF:

0.119

Gnomad4 OTH

AF:

0.0993

Alfa

AF:

0.119

Hom.:

1282

Bravo

AF:

0.0885

TwinsUK

AF:

0.117

AC:

433

ALSPAC

AF:

0.116

AC:

447

ESP6500AA

AF:

0.0429

AC:

189

ESP6500EA

AF:

0.121

AC:

1044

ExAC

AF:

0.0926

AC:

11249

Asia WGS

AF:

0.0340

AC:

119

AN:

3478

EpiCase

AF:

0.131

EpiControl

AF:

0.134

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 15774581) -

Type 2 diabetes mellitus

Pathogenic:1

Likely risk allele, criteria provided, single submitter

research

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

KLF11 gene mutations are associated with MODY, however it needs further validation via clinical studies. This particular variant (rs35927125) of KLF11 gene can trigger Type II Diabetes Mellitus. However, more studies are required in different ethnic groups to ascertain its significance. -

Maturity-onset diabetes of the young type 7

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.48

Cadd

Benign

Dann

Benign

0.97

DEOGEN2

Benign

0.11

T;T;.;.;T;.

Eigen

Benign

-0.48

Eigen_PC

Benign

-0.48

FATHMM_MKL

Uncertain

0.78

LIST_S2

Benign

0.44

T;T;T;T;T;.

MetaRNN

Benign

0.0015

T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationTaster

Benign

0.78

P;P;P

PrimateAI

Benign

0.38

PROVEAN

Benign

-1.7

N;N;N;N;N;N

REVEL

Benign

0.069

Sift

Benign

0.23

T;D;T;T;T;T

Sift4G

Benign

0.11

T;T;T;T;T;T

Polyphen

0.0030

.;B;.;.;.;.

Vest4

0.077, 0.097, 0.091

MPC

0.022

ClinPred

0.0058

GERP RS

-0.46

Varity_R

0.12

gMVP

0.11

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