NM_003597.5:c.1039G>T

Variant names:

• chr2-10048376-G-T
• rs121912645
• NM_003597.5:c.1039G>T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6 BS2

The NM_003597.5(KLF11):​c.1039G>T​(p.Ala347Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000819 in 1,612,500 control chromosomes in the GnomAD database, with no homozygous occurrence. 14/21 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 0.000079 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000082 (0 hom.)
• Consequence: KLF11 NM_003597.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2 B:1
• Conservation: PhyloP100: -0.265

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]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP6: Variant 2-10048376-G-T is Benign according to our data. Variant chr2-10048376-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 6498.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.
• BS2: High AC in GnomAd4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLF11	NM_003597.5	c.1039G>T	p.Ala347Ser	missense_variant	Exon 3 of 4	ENST00000305883.6	NP_003588.1
KLF11	NM_001177716.2	c.988G>T	p.Ala330Ser	missense_variant	Exon 3 of 4		NP_001171187.1
KLF11	NM_001177718.2	c.988G>T	p.Ala330Ser	missense_variant	Exon 3 of 4		NP_001171189.1
KLF11	XM_047446025.1	c.988G>T	p.Ala330Ser	missense_variant	Exon 3 of 4		XP_047301981.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLF11	ENST00000305883.6	c.1039G>T	p.Ala347Ser	missense_variant	Exon 3 of 4	1	NM_003597.5	ENSP00000307023.1
KLF11	ENST00000535335.1	c.988G>T	p.Ala330Ser	missense_variant	Exon 3 of 4	2		ENSP00000442722.1
KLF11	ENST00000540845.5	c.988G>T	p.Ala330Ser	missense_variant	Exon 3 of 4	2		ENSP00000444690.1

Frequencies

GnomAD3 genomes AF: 0.0000788 AC: 12 AN: 152222 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

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: 0.0000882

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000132 AC: 33 AN: 250908 Hom.: 0 AF XY: 0.000147 AC XY: 20 AN XY: 135598

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000463

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: 0.000132

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000822 AC: 120 AN: 1460278 Hom.: 0 Cov.: 36 AF XY: 0.0000992 AC XY: 72 AN XY: 726160

Gnomad4 AFR exome AF: 0.0000897

Gnomad4 AMR exome AF: 0.000604

Gnomad4 ASJ exome AF: 0.0000768

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000720

Gnomad4 OTH exome AF: 0.0000829

GnomAD4 genome AF: 0.0000788 AC: 12 AN: 152222 Hom.: 0 Cov.: 33 AF XY: 0.0000672 AC XY: 5 AN XY: 74372

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000118 Hom.: 0

Bravo AF: 0.000178

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000115 AC: 14

EpiCase AF: 0.000273

EpiControl AF: 0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Maturity-onset diabetes of the young type 7 Pathogenic:1 Uncertain:1

Mar 29, 2005

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

May 22, 2022

3billion

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an allele frequency greater than expected (0.01%) for the associated disorder in the gnomAD v2.1.1 dataset and therefore considered uncertain significant. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 15774581). In silico tool predictions suggest no damaging effect of the variant on gene or gene product (REVEL: 0.18; 3Cnet: 0.00). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with KLF11 related disorder (ClinVar ID: VCV000006498 / PMID: 15774581). However, the evidence of pathogenicity is insufficient at this time. Therefore, this variant is classified as uncertain significance according to the recommendation of ACMG/AMP guideline. -

not provided Uncertain:1 Benign:1

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

KLF11: BP4 -

Jan 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 347 of the KLF11 protein (p.Ala347Ser). This variant is present in population databases (rs121912645, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features of KLF11-related conditions (PMID: 15774581, 29758564, 35108381). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 6498). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Experimental studies have shown that this missense change affects KLF11 function (PMID: 15774581, 23589285, 31124255). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	0.023
DANN	Benign	0.94
DEOGEN2	Benign	0.15	T;.;.
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.61	T;T;.
M_CAP	Benign	0.0045	T
MetaRNN	Uncertain	0.62	D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L;.;.
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.3	N;N;N
REVEL	Benign	0.18
Sift	Benign	0.12	T;T;T
Sift4G	Benign	0.24	T;T;T
Polyphen		0.13	B;.;.
Vest4		0.66
MVP		0.44
MPC		0.022
ClinPred		0.013	T
GERP RS		0.88
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.054
gMVP		0.23

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

Other links and lift over

dbSNP: rs121912645; hg19: chr2-10188503;