rs373763254
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Variant summary
Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2
The NM_194454.3(KRIT1):c.846-5_846-4insA variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000422 in 1,611,962 control chromosomes in the GnomAD database, including 6 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.0021 ( 4 hom., cov: 32)
Exomes 𝑓: 0.00024 ( 2 hom. )
Consequence
KRIT1
NM_194454.3 splice_region, splice_polypyrimidine_tract, intron
NM_194454.3 splice_region, splice_polypyrimidine_tract, intron
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.512
Genes affected
KRIT1 (HGNC:1573): (KRIT1 ankyrin repeat containing) This gene encodes a protein containing four ankyrin repeats, a band 4.1/ezrin/radixin/moesin (FERM) domain, and multiple NPXY sequences. The encoded protein is localized in the nucleus and cytoplasm. It binds to integrin cytoplasmic domain-associated protein-1 alpha (ICAP1alpha), and plays a critical role in beta1-integrin-mediated cell proliferation. It associates with junction proteins and RAS-related protein 1A (Rap1A), which requires the encoded protein for maintaining the integrity of endothelial junctions. It is also a microtubule-associated protein and may play a role in microtubule targeting. Mutations in this gene result in cerebral cavernous malformations. Multiple alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Sep 2009]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -16 ACMG points.
BP6
?
Variant 7-92234596-A-AT is Benign according to our data. Variant chr7-92234596-A-AT is described in ClinVar as [Likely_benign]. Clinvar id is 360888.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
?
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00213 (325/152302) while in subpopulation AFR AF= 0.00722 (300/41560). AF 95% confidence interval is 0.00655. There are 4 homozygotes in gnomad4. There are 161 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
High AC in GnomAd4 at 325 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KRIT1 | NM_194454.3 | c.846-5_846-4insA | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | ENST00000394505.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KRIT1 | ENST00000394505.7 | c.846-5_846-4insA | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | 1 | NM_194454.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00204 AC: 311AN: 152184Hom.: 3 Cov.: 32
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GnomAD3 exomes AF: 0.000527 AC: 132AN: 250642Hom.: 0 AF XY: 0.000442 AC XY: 60AN XY: 135804
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GnomAD4 exome AF: 0.000243 AC: 355AN: 1459660Hom.: 2 Cov.: 30 AF XY: 0.000204 AC XY: 148AN XY: 726328
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GnomAD4 genome ? AF: 0.00213 AC: 325AN: 152302Hom.: 4 Cov.: 32 AF XY: 0.00216 AC XY: 161AN XY: 74468
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Cerebral cavernous malformation Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Oct 28, 2023 | - - |
Angiokeratoma corporis diffusum with arteriovenous fistulas Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
KRIT1-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jul 27, 2020 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Dec 01, 2023 | ENSG00000285953: BS2; ENSG00000289027: BS2 - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at