chr2-10043751-C-A

Variant names:

• chr2-10043751-C-A
• NM_003597.5:c.35C>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003597.5(KLF11):​c.35C>A​(p.Ala12Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KLF11 NM_003597.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 1.78

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13318682).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLF11	NM_003597.5	c.35C>A	p.Ala12Glu	missense_variant	Exon 1 of 4	ENST00000305883.6	NP_003588.1
KLF11	NM_001177716.2	c.-146C>A		upstream_gene_variant			NP_001171187.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLF11	ENST00000305883.6	c.35C>A	p.Ala12Glu	missense_variant	Exon 1 of 4	1	NM_003597.5	ENSP00000307023.1
KLF11	ENST00000401510.5	c.-10+680C>A		intron_variant	Intron 1 of 2	3		ENSP00000386058.1
KLF11	ENST00000540845.5	c.-146C>A		upstream_gene_variant		2		ENSP00000444690.1
KLF11	ENST00000448523.5	c.-146C>A		upstream_gene_variant		4		ENSP00000387866.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1233308 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 608810

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

KLF11-related disorder Uncertain:1

Jan 19, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The KLF11 c.35C>A variant is predicted to result in the amino acid substitution p.Ala12Glu. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not provided Uncertain:1

Jun 12, 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 glutamic acid, which is acidic and polar, at codon 12 of the KLF11 protein (p.Ala12Glu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with KLF11-related conditions. 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. 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	0.22
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	18
DANN	Benign	0.95
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.47	T
M_CAP	Uncertain	0.092	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.96	N
REVEL	Benign	0.015
Sift	Uncertain	0.017	D
Sift4G	Benign	0.55	T
Polyphen		0.29	B
Vest4		0.27
MutPred		0.15		Gain of disorder (P = 0.0636);
MVP		0.56
MPC		0.046
ClinPred		0.15	T
GERP RS		1.7
Varity_R		0.11
gMVP		0.40

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-10183878;