rs1554514380

Variant names:

• chr7-92222976-ATAC-A
• rs1554514380
• NM_194454.3:c.1255-1_1256delGTA

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 rank	MANE	Protein	UniProt
KRIT1	NM_194454.3	c.1255-1_1256delGTA	p.Tyr419fs	frameshift_variant, splice_acceptor_variant, splice_region_variant, intron_variant	Exon 13 of 19	ENST00000394505.7	NP_919436.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRIT1	ENST00000394505.7	c.1255-1_1256delGTA	p.Tyr419fs	frameshift_variant, splice_acceptor_variant, splice_region_variant, intron_variant	Exon 13 of 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	Exon 13 of 26			ENSP00000510568.1
ENSG00000285953	ENST00000458493.6	c.1255-1_1256delGTA	p.Tyr419fs	frameshift_variant, splice_acceptor_variant, splice_region_variant, intron_variant	Exon 12 of 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

Dec 07, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). For these reasons, this variant has been classified as Pathogenic. -

Aug 17, 2022

Genetics and Molecular Pathology, SA Pathology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

KRIT1-related disorder Pathogenic:1

Sep 27, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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;