rs121912645
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2
The ENST00000305883.6(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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A347T) has been classified as Uncertain significance.
Frequency
Consequence
ENST00000305883.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
KLF11 | NM_003597.5 | c.1039G>T | p.Ala347Ser | missense_variant | 3/4 | ENST00000305883.6 | NP_003588.1 | |
KLF11 | NM_001177716.2 | c.988G>T | p.Ala330Ser | missense_variant | 3/4 | NP_001171187.1 | ||
KLF11 | NM_001177718.2 | c.988G>T | p.Ala330Ser | missense_variant | 3/4 | NP_001171189.1 | ||
KLF11 | XM_047446025.1 | c.988G>T | p.Ala330Ser | missense_variant | 3/4 | XP_047301981.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
KLF11 | ENST00000305883.6 | c.1039G>T | p.Ala347Ser | missense_variant | 3/4 | 1 | NM_003597.5 | ENSP00000307023 | A2 | |
KLF11 | ENST00000535335.1 | c.988G>T | p.Ala330Ser | missense_variant | 3/4 | 2 | ENSP00000442722 | P4 | ||
KLF11 | ENST00000540845.5 | c.988G>T | p.Ala330Ser | missense_variant | 3/4 | 2 | ENSP00000444690 | P4 |
Frequencies
GnomAD3 genomes AF: 0.0000788 AC: 12AN: 152222Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000132 AC: 33AN: 250908Hom.: 0 AF XY: 0.000147 AC XY: 20AN XY: 135598
GnomAD4 exome AF: 0.0000822 AC: 120AN: 1460278Hom.: 0 Cov.: 36 AF XY: 0.0000992 AC XY: 72AN XY: 726160
GnomAD4 genome AF: 0.0000788 AC: 12AN: 152222Hom.: 0 Cov.: 33 AF XY: 0.0000672 AC XY: 5AN XY: 74372
ClinVar
Submissions by phenotype
Maturity-onset diabetes of the young type 7 Pathogenic:1Uncertain:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 29, 2005 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | 3billion | May 22, 2022 | 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
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 18, 2024 | 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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at