chr15-89649809-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_198525.3(KIF7):c.461G>A(p.Arg154Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000909 in 1,551,792 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_198525.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KIF7 | NM_198525.3 | c.461G>A | p.Arg154Gln | missense_variant | 3/19 | ENST00000394412.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KIF7 | ENST00000394412.8 | c.461G>A | p.Arg154Gln | missense_variant | 3/19 | 5 | NM_198525.3 | P2 | |
KIF7 | ENST00000445906.1 | c.*120G>A | 3_prime_UTR_variant, NMD_transcript_variant | 3/5 | 1 | ||||
KIF7 | ENST00000696512.1 | c.584G>A | p.Arg195Gln | missense_variant | 3/19 | A2 |
Frequencies
GnomAD3 genomes AF: 0.000493 AC: 75AN: 152232Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000108 AC: 17AN: 156920Hom.: 0 AF XY: 0.0000602 AC XY: 5AN XY: 83116
GnomAD4 exome AF: 0.0000472 AC: 66AN: 1399442Hom.: 0 Cov.: 31 AF XY: 0.0000333 AC XY: 23AN XY: 690230
GnomAD4 genome AF: 0.000492 AC: 75AN: 152350Hom.: 0 Cov.: 33 AF XY: 0.000537 AC XY: 40AN XY: 74492
ClinVar
Submissions by phenotype
not provided Uncertain:4
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jun 21, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Jun 06, 2023 | PM2 - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 15, 2020 | Reported previously in the heterozygous state with a second KIF7 variant in an individual with features of acrocallosal syndrome (Tunovic et al., 2015).; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26633542, 25131622, 26174511) - |
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The KIF7 p.Arg154Gln variant was identified in two individuals with neurodevelopmental features similar to acrocallosal syndrome (Tunovic_2015_PMID:26174511; Srivastava_2014_PMID:25131622). These individuals were compound heterozygous for the KIF7 p.Arg154Gln variant and either p.Glu987Lys or p.E987K. The variant was identified in dbSNP (ID: rs180758272) and ClinVar (classified as uncertain significance by Invitae and EGL Genetic Diagnostics). The variant was identified in control databases in 31 of 188318 chromosomes at a frequency of 0.0001646 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: African in 26 of 16664 chromosomes (freq: 0.00156), Latino in 3 of 25532 chromosomes (freq: 0.000118) and European (non-Finnish) in 2 of 76266 chromosomes (freq: 0.000026), but was not observed in the Ashkenazi Jewish, East Asian, European (Finnish), Other, or South Asian populations. The p.Arg154 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. - |
KIF7-related ciliopathy spectrum disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Oct 29, 2019 | The KIF7 c.461G>A (p.Arg154Gln) missense variant has been reported in one study in which it is identified in a heterozygous state of unknown inheritance in one individual with KIF7-related ciliopathy spectrum disorder. The affected individual also carried a second missense variant in the KIF7 gene in a heterozygous state, which was shown to be maternally inherited. Paternal DNA was not available for testing (Tunovic et al. 2015). The p.Arg154Gln variant is reported at a frequency of 0.001560 in the African population of the Genome Aggregation Database in a region of good sequence coverage. The Arg154 residue is located in the kinesin motor domain. Based on the limited evidence, the p.Arg154Gln variant is classified as a variant of unknown significance for KIF7-related ciliopathy spectrum disorder. - |
Acrocallosal syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 27, 2022 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 154 of the KIF7 protein (p.Arg154Gln). This variant is present in population databases (rs180758272, gnomAD 0.2%). This missense change has been observed in individual(s) with acrocallosal syndrome (PMID: 26174511). ClinVar contains an entry for this variant (Variation ID: 463144). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt KIF7 protein function. 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at