rs752248403
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP3_Moderate
The NM_198525.3(KIF7):βc.2896_2897delβ(p.Ala966ProfsTer81) variant causes a frameshift, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000226 in 1,550,916 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (β β ). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_198525.3 frameshift, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
KIF7 | NM_198525.3 | c.2896_2897del | p.Ala966ProfsTer81 | frameshift_variant, splice_region_variant | 15/19 | ENST00000394412.8 | NP_940927.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
KIF7 | ENST00000394412.8 | c.2896_2897del | p.Ala966ProfsTer81 | frameshift_variant, splice_region_variant | 15/19 | 5 | NM_198525.3 | ENSP00000377934 | P2 | |
KIF7 | ENST00000696512.1 | c.3019_3020del | p.Ala1007ProfsTer81 | frameshift_variant, splice_region_variant | 15/19 | ENSP00000512678 | A2 | |||
KIF7 | ENST00000677187.1 | n.570_571del | splice_region_variant, non_coding_transcript_exon_variant | 3/7 |
Frequencies
GnomAD3 genomes AF: 0.0000591 AC: 9AN: 152214Hom.: 0 Cov.: 34
GnomAD3 exomes AF: 0.00000646 AC: 1AN: 154882Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 82476
GnomAD4 exome AF: 0.0000186 AC: 26AN: 1398702Hom.: 0 AF XY: 0.0000101 AC XY: 7AN XY: 689740
GnomAD4 genome AF: 0.0000591 AC: 9AN: 152214Hom.: 0 Cov.: 34 AF XY: 0.0000134 AC XY: 1AN XY: 74362
ClinVar
Submissions by phenotype
Acrocallosal syndrome Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 01, 2011 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | May 16, 2017 | This sequence change deletes 2 nucleotides in exon 15 of the KIF7 mRNA (c.2896_2897delGC), causing a frameshift at codon 966. This creates a premature translational stop signal (p.Ala966Profs*81) and is expected to result in an absent or disrupted protein product. Loss-of-function variants in KIF7 are known to be pathogenic. This particular variant has been reported to be homozygous in individuals affected with fetal hydrolethalus and acrocallosal syndromes (PMID: 215522264), as well as an individual with facial dysmorphism, intellectual disability, and dysgenesis of corpus callosum (PMID: 27081521). For these reasons, this variant has been classified as Pathogenic. - |
Hydrolethalus syndrome 2 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 01, 2011 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 09, 2023 | Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21552264, 27081521, 27894351, 31589614, 34884862) - |
Multiple epiphyseal dysplasia, Al-Gazali type Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | DASA | Mar 05, 2022 | The c.2896_2897delGC;p.(Ala966Profs*81) is a null frameshift variant (NMD) in the KIF7 gene and predicts alteration of the nonsense-mediate decay - NMD is present in a relevant exon to the transcript - PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 30895; PMID: 21552264) - PS4. The variant is present at low allele frequencies population databases (rs752248403 β gnomAD 0.00006457%; ABraOM 0.000854 frequency - http://abraom.ib.usp.br/) - PM2_supporting. In summary, the currently available evidence indicates that the variant is pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at