chr2-10048376-G-A

Variant names:

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

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_003597.5(KLF11):​c.1039G>A​(p.Ala347Thr) 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: KLF11 NM_003597.5 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U: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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.067498654).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLF11	NM_003597.5	c.1039G>A	p.Ala347Thr	missense_variant	Exon 3 of 4	ENST00000305883.6	NP_003588.1
KLF11	NM_001177716.2	c.988G>A	p.Ala330Thr	missense_variant	Exon 3 of 4		NP_001171187.1
KLF11	NM_001177718.2	c.988G>A	p.Ala330Thr	missense_variant	Exon 3 of 4		NP_001171189.1
KLF11	XM_047446025.1	c.988G>A	p.Ala330Thr	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>A	p.Ala347Thr	missense_variant	Exon 3 of 4	1	NM_003597.5	ENSP00000307023.1
KLF11	ENST00000535335.1	c.988G>A	p.Ala330Thr	missense_variant	Exon 3 of 4	2		ENSP00000442722.1
KLF11	ENST00000540845.5	c.988G>A	p.Ala330Thr	missense_variant	Exon 3 of 4	2		ENSP00000444690.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

KLF11-related disorder Uncertain:1

Jun 11, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The KLF11 c.1039G>A variant is predicted to result in the amino acid substitution p.Ala347Thr. To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. This variant has been confirmed de novo in an individual with type I diabetes mellitus (Internal Data, PreventionGenetics). Another amino acid substitution at this position (p.Ala347Ser) has been reported to segregate with type 2 diabetes mellitus/glucose intolerance in a four generation family described as having a MODY-like phenotype (Neve et al. 2005. PubMed ID: 15774581) and functional studies demonstrated that this variant impairs protein function (Lomberk et al. 2013. PubMed ID: 23589285). At this time, the clinical significance of p.Ala347Thr is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	0.15
DANN	Benign	0.82
DEOGEN2	Benign	0.13	T;.;.
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.55	T;T;.
M_CAP	Benign	0.0047	T
MetaRNN	Benign	0.067	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.79	N;.;.
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.88	N;N;N
REVEL	Benign	0.0080
Sift	Benign	0.42	T;T;T
Sift4G	Benign	0.31	T;T;T
Polyphen		0.051	B;.;.
Vest4		0.088
MutPred		0.26		Gain of glycosylation at A347 (P = 0.0023);.;.;
MVP		0.36
MPC		0.021
ClinPred		0.10	T
GERP RS		0.88
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.031
gMVP		0.25

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: chr2-10188503;