rs372235519
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong
The NM_007059.4(KPTN):c.1250G>A(p.Arg417His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000229 in 1,613,398 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 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. R417C) has been classified as Likely benign.
Frequency
Consequence
NM_007059.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KPTN | NM_007059.4 | c.1250G>A | p.Arg417His | missense_variant | 12/12 | ENST00000338134.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KPTN | ENST00000338134.8 | c.1250G>A | p.Arg417His | missense_variant | 12/12 | 1 | NM_007059.4 | P1 | |
ENST00000669287.1 | n.69-985C>T | intron_variant, non_coding_transcript_variant | |||||||
KPTN | ENST00000600551.1 | n.141G>A | non_coding_transcript_exon_variant | 2/2 | 5 | ||||
KPTN | ENST00000594208.5 | c.*884G>A | 3_prime_UTR_variant, NMD_transcript_variant | 13/13 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152224Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000121 AC: 3AN: 248534Hom.: 0 AF XY: 0.00000741 AC XY: 1AN XY: 134894
GnomAD4 exome AF: 0.0000226 AC: 33AN: 1461174Hom.: 0 Cov.: 31 AF XY: 0.0000165 AC XY: 12AN XY: 726846
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152224Hom.: 0 Cov.: 31 AF XY: 0.0000403 AC XY: 3AN XY: 74366
ClinVar
Submissions by phenotype
Macrocephaly-developmental delay syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 09, 2019 | 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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The histidine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with KPTN-related disease. This variant is present in population databases (rs372235519, ExAC 0.01%). This sequence change replaces arginine with histidine at codon 417 of the KPTN protein (p.Arg417His). The arginine residue is weakly conserved and there is a small physicochemical difference between arginine and histidine. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 13, 2023 | The c.1250G>A (p.R417H) alteration is located in exon 12 (coding exon 12) of the KPTN gene. This alteration results from a G to A substitution at nucleotide position 1250, causing the arginine (R) at amino acid position 417 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at