rs758361736
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5
The NM_198525.3(KIF7):āc.434A>Cā(p.Tyr145Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000135 in 1,551,662 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_198525.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
KIF7 | ENST00000394412.8 | c.434A>C | p.Tyr145Ser | missense_variant | Exon 3 of 19 | 5 | NM_198525.3 | ENSP00000377934.3 | ||
KIF7 | ENST00000445906.1 | n.*93A>C | non_coding_transcript_exon_variant | Exon 3 of 5 | 1 | ENSP00000395906.1 | ||||
KIF7 | ENST00000445906.1 | n.*93A>C | 3_prime_UTR_variant | Exon 3 of 5 | 1 | ENSP00000395906.1 | ||||
KIF7 | ENST00000696512.1 | c.557A>C | p.Tyr186Ser | missense_variant | Exon 3 of 19 | ENSP00000512678.1 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152234Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000128 AC: 2AN: 156816Hom.: 0 AF XY: 0.0000241 AC XY: 2AN XY: 83074
GnomAD4 exome AF: 0.0000136 AC: 19AN: 1399428Hom.: 0 Cov.: 31 AF XY: 0.0000159 AC XY: 11AN XY: 690224
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152234Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74360
ClinVar
Submissions by phenotype
Acrocallosal syndrome Pathogenic:1Uncertain:1
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This sequence change replaces tyrosine, which is neutral and polar, with serine, which is neutral and polar, at codon 145 of the KIF7 protein (p.Tyr145Ser). This variant is present in population databases (rs758361736, gnomAD 0.003%). This missense change has been observed in individual(s) with clinical features of acrocallosal syndrome (PMID: 29286531). ClinVar contains an entry for this variant (Variation ID: 374124). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt KIF7 protein function with a negative predictive value of 80%. 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. -
Cerebellar ataxia;C0026838:Spasticity;C0028738:Nystagmus;C0038379:Strabismus;C0431904:Postaxial hand polydactyly;C2112129:Postaxial foot polydactyly;C3278923:Ventriculomegaly Pathogenic:1
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Male infertility due to gonadal dysgenesis or sperm disorder Pathogenic:1
In addition, the same case carried two additional variants: SOS2 c.26A>G p.E9G and CHEK1 c.1036C>T p.Q346Ter, indicating an oligogenic effect. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at