rs1554514380

Positions:

• chr7-92222976-ATAC-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_194454.3(KRIT1):​c.1255-1_1256delGTA​(p.Tyr419fs) variant causes a frameshift, splice acceptor, splice region, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000069 in 1,449,596 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 (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: KRIT1 NM_194454.3 frameshift, splice_acceptor, splice_region, intron
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.03

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]

ENSG00000289027 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-92222976-ATAC-A is Pathogenic according to our data. Variant chr7-92222976-ATAC-A is described in ClinVar as [Pathogenic]. Clinvar id is 468206.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-92222976-ATAC-A is described in Lovd as [Pathogenic]. Variant chr7-92222976-ATAC-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRIT1	NM_194454.3	c.1255-1_1256delGTA	p.Tyr419fs	frameshift_variant, splice_acceptor_variant, splice_region_variant, intron_variant	13/19	ENST00000394505.7	NP_919436.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRIT1	ENST00000394505.7	c.1255-1_1256delGTA	p.Tyr419fs	frameshift_variant, splice_acceptor_variant, splice_region_variant, intron_variant	13/19	1	NM_194454.3	ENSP00000378013.2
ENSG00000289027	ENST00000692281.1	c.1255-1_1256delGTA	p.Tyr419fs	frameshift_variant, splice_acceptor_variant, splice_region_variant, intron_variant	13/26			ENSP00000510568.1
ENSG00000285953	ENST00000458493.6	c.1255-1_1256delGTA	p.Tyr419fs	frameshift_variant, splice_acceptor_variant, splice_region_variant, intron_variant	12/20	4		ENSP00000396352.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.90e-7 AC: 1 AN: 1449596 Hom.: 0 AF XY: 0.00000139 AC XY: 1 AN XY: 722022

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.08e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cerebral cavernous malformation Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Aug 17, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 13, 2022	This variant results in the deletion of part of exon 14 (c.1255-1_1256del) of the KRIT1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in KRIT1 are known to be pathogenic (PMID: 10508515, 11222804, 12404106, 24689081). This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with cerebral cavernous malformations (PMID: 11914398, 18300272, 24689081). It has also been observed to segregate with disease in related individuals. This variant is also known as IVS13-2delATG. ClinVar contains an entry for this variant (Variation ID: 468206). 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. -

KRIT1-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 27, 2023

The KRIT1 c.1255-1_1256delGTA variant is predicted to result in a deletion affecting a canonical splice site. This variant is predicted to result in an intronic in-frame deletion. This deletion of three nucleotides abolishes the consensus splice acceptor signal and is predicted to result in aberrant splicing (SpliceAI, Jaganathan K, et al. 2019. PubMed ID: 30661751). This variant has been reported multiple times to be causative for cerebral cavernous malformations (CCMs) (Verlaan et al. 2002. PubMed ID: 11914398; Stahl et al. 2008. PubMed ID: 18300272). We have also observed this deletion in several other affected patients at PreventionGenetics. This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.25		Position offset: -8
DS_AL_spliceai		0.98		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1554514380; hg19: chr7-91852290;