rs752248403
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_198525.3(KIF7):โc.2896_2897delGCโ(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 (โ โ ). 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 18 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
KIF7 | ENST00000394412.8 | c.2896_2897delGC | p.Ala966ProfsTer81 | frameshift_variant, splice_region_variant | Exon 15 of 19 | 5 | NM_198525.3 | ENSP00000377934.3 | ||
KIF7 | ENST00000696512.1 | c.3019_3020delGC | p.Ala1007ProfsTer81 | frameshift_variant, splice_region_variant | Exon 15 of 19 | ENSP00000512678.1 | ||||
KIF7 | ENST00000677187.1 | n.570_571delGC | splice_region_variant, non_coding_transcript_exon_variant | Exon 3 of 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, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jun 17, 2024 | This sequence change creates a premature translational stop signal (p.Ala966Profs*81) in the KIF7 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in KIF7 are known to be pathogenic (PMID: 19666503, 21552264, 21633164, 26648833). This variant is present in population databases (rs752248403, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with KIF7-related conditions (PMID: 21552264, 27081521). ClinVar contains an entry for this variant (Variation ID: 30895). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 01, 2011 | - - |
Hydrolethalus syndrome 2 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 01, 2011 | - - |
Acrocallosal syndrome;C1846722:Multiple epiphyseal dysplasia, Al-Gazali type;C3279899:Hydrolethalus syndrome 2 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jun 24, 2024 | - - |
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 โ 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