2-207124097-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP5
The NM_003709.4(KLF7):c.410C>T(p.Thr137Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_003709.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
KLF7 | NM_003709.4 | c.410C>T | p.Thr137Met | missense_variant | Exon 2 of 4 | ENST00000309446.11 | NP_003700.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251442Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135894
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461888Hom.: 0 Cov.: 36 AF XY: 0.00000138 AC XY: 1AN XY: 727244
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
KLF7-related neurodevelopmental disorder Pathogenic:1
- -
Inborn genetic diseases Pathogenic:1
The c.410C>T (p.T137M) alteration is located in exon 2 (coding exon 2) of the KLF7 gene. This alteration results from a C to T substitution at nucleotide position 410, causing the threonine (T) at amino acid position 137 to be replaced by a methionine (M). Based on data from gnomAD, the T allele has an overall frequency of <0.001% (1/251442) total alleles studied. The highest observed frequency was 0.003% (1/34588) of Latino alleles. This variant has been determined to be the result of a de novo mutation in multiple individuals with similar features such as developmental delay, motor delay, speech delay, gait disturbances, and dysmorphic features (Powis, 2018; DECIPHER; External communication). This amino acid position is highly conserved in available vertebrate species. The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic. -
Anxiety;C3714756:Intellectual disability Pathogenic:1
Gene is not yet OMIM morbid, but a first cohort is published PMID : 29251763 -
not provided Pathogenic:1
Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. For these reasons, this variant has been classified as Pathogenic. This variant has been observed in individual(s) with a neurodevelopmental condition (PMID: 29251763, Invitae). In at least one individual the variant was observed to be de novo. This sequence change replaces threonine with methionine at codon 137 of the KLF7 protein (p.Thr137Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. -
Neurodevelopmental disorder Pathogenic:1
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely Pathogenic. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. Mice deficient in KLF7 had neonatal death and and widespread neurological defects suggesting loss of function, while missense variants at important residues in the CPD motif were show to create a more stable protein that could not be phosphorylated or ubiquitylated suggesting gain of function (PMID: 30838725). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from threonine to methionine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0601 - Variant is located in the well-established functional CPD motif and affects the conserved Thr residue. Functional studies in HEK293T cells showed that a mutant KLF7 with both p.(Thr137Ala) and p.(Ser141Ala) could not be phosphorylated or ubiquitylated leading to a more stable protein (PMID: 30838725). (SP) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in at least five de novo individuals with KLF7-related disorders (DECIPHER, PMID: 29251763). Additional pathogenic, likely pathogenic and VUS cases have also been reported in ClinVar. (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Delayed gross motor development;C3532934:Mild expressive language delay Pathogenic:1
This variant was identified as de novo (maternity and paternity confirmed)._x000D_ Criteria applied: PS2_STR, PS4_SUP, PP3 -
KLF7-related disorder Uncertain:1
PS2, BS2, PP3 -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at