rs1554539120

Positions:

• chr7-92242135-T-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

The ENST00000394505.7(KRIT1):​c.1A>G​(p.Met1?) variant causes a start lost, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000143 in 1,400,016 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: KRIT1 ENST00000394505.7 start_lost, splice_region
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.34

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-92242135-T-C is Pathogenic according to our data. Variant chr7-92242135-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 468215.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRIT1	NM_194454.3	c.1A>G	p.Met1?	start_lost, splice_region_variant	4/19	ENST00000394505.7	NP_919436.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRIT1	ENST00000394505.7	c.1A>G	p.Met1?	start_lost, splice_region_variant	4/19	1	NM_194454.3	ENSP00000378013	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1400016 Hom.: 0 Cov.: 23 AF XY: 0.00000286 AC XY: 2 AN XY: 700378

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: 0.00000189

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 23, 2024	Initiation codon variant in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34556564) -
Likely pathogenic, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Feb 15, 2017	- -

Cerebral cavernous malformation Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 13, 2021

In summary, this is a novel variant that affects the initiator codon of KRIT1, and has been observed in an affected individual. This evidence strongly suggests that the variant is pathogenic, but the available data is currently insufficient to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. This variant has been observed in an individual with features of cerebral cavernous malformations (Invitae database), which suggests that this variant may contribute to disease. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a KRIT1-related disease. This sequence change affects the initiator methionine of the KRIT1 mRNA. The next in-frame methionine is located at c.280 (p.Met94). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Benign	0.27	.;T;T;T;T;.;T;T;.;T;.;T;T;T;.;.;.;.
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.90	D;D;.;.;.;D;D;D;D;D;D;D;D;D;D;D;D;.
M_CAP	Pathogenic	0.79	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.12	T
MutationTaster	Benign	1.0	D;D;D;D;D
PROVEAN	Benign	-1.0	.;N;N;N;N;N;D;D;D;D;D;D;D;D;D;D;D;D
REVEL	Uncertain	0.60
Sift	Pathogenic	0.0	.;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.;.
Sift4G	Pathogenic	0.0	.;D;D;D;D;D;D;.;.;D;.;.;.;D;D;D;D;.
Polyphen		0.0020	.;B;B;B;B;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.90, 0.93, 0.91, 0.88
MutPred		1.0		Loss of helix (P = 0.079);Loss of helix (P = 0.079);Loss of helix (P = 0.079);Loss of helix (P = 0.079);Loss of helix (P = 0.079);Loss of helix (P = 0.079);Loss of helix (P = 0.079);Loss of helix (P = 0.079);Loss of helix (P = 0.079);Loss of helix (P = 0.079);Loss of helix (P = 0.079);Loss of helix (P = 0.079);Loss of helix (P = 0.079);Loss of helix (P = 0.079);Loss of helix (P = 0.079);Loss of helix (P = 0.079);Loss of helix (P = 0.079);Loss of helix (P = 0.079);
MVP		0.90
ClinPred		0.99	D
GERP RS		6.0
Varity_R		0.74
gMVP		0.59

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.99		Position offset: -1

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

Publications

LitVar

Other links and lift over

dbSNP: rs1554539120; hg19: chr7-91871449;