rs574142144

Variant names:

• chr7-92237636-TAA-T
• rs574142144
• NM_194454.3:c.355+29_355+30delTT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_194454.3(KRIT1):​c.355+29_355+30delTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00042 in 1,291,334 control chromosomes in the GnomAD database, including 4 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0018 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00023 (2 hom.)
• Consequence: KRIT1 NM_194454.3 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.565
• Publications: 0 publications found

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]

KRIT1 Gene-Disease associations (from GenCC):

• cerebral cavernous malformation 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• famililal cerebral cavernous malformations

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000289027 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP6: Variant 7-92237636-TAA-T is Benign according to our data. Variant chr7-92237636-TAA-T is described in ClinVar as Likely_benign. ClinVar VariationId is 263099.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00183 (278/152202) while in subpopulation AFR AF = 0.00626 (260/41562). AF 95% confidence interval is 0.00563. There are 2 homozygotes in GnomAd4. There are 139 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 278 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRIT1	NM_194454.3	c.355+29_355+30delTT		intron_variant	Intron 6 of 18	ENST00000394505.7	NP_919436.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRIT1	ENST00000394505.7	c.355+29_355+30delTT		intron_variant	Intron 6 of 18	1	NM_194454.3	ENSP00000378013.2
ENSG00000289027	ENST00000692281.1	c.355+29_355+30delTT		intron_variant	Intron 6 of 25			ENSP00000510568.1
ENSG00000285953	ENST00000458493.6	c.355+29_355+30delTT		intron_variant	Intron 5 of 19	4		ENSP00000396352.2

Frequencies

GnomAD3 genomes AF: 0.00176 AC: 267 AN: 152084 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00601

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000852

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000471 AC: 117 AN: 248444 AF XY: 0.000409

Gnomad AFR exome AF: 0.00600

Gnomad AMR exome AF: 0.000497

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000178

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.000232 AC: 264 AN: 1139132 Hom.: 2 AF XY: 0.000194 AC XY: 113 AN XY: 581704

African (AFR) AF: 0.00768 AC: 210 AN: 27328

American (AMR) AF: 0.000476 AC: 21 AN: 44150

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24086

East Asian (EAS) AF: 0.00 AC: 0 AN: 38010

South Asian (SAS) AF: 0.0000379 AC: 3 AN: 79110

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53044

Middle Eastern (MID) AF: 0.000779 AC: 4 AN: 5132

European-Non Finnish (NFE) AF: 0.00000244 AC: 2 AN: 818702

Other (OTH) AF: 0.000484 AC: 24 AN: 49570

GnomAD4 genome AF: 0.00183 AC: 278 AN: 152202 Hom.: 2 Cov.: 32 AF XY: 0.00187 AC XY: 139 AN XY: 74420

African (AFR) AF: 0.00626 AC: 260 AN: 41562

American (AMR) AF: 0.000851 AC: 13 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10584

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 67968

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.00113 Hom.: 0

Bravo AF: 0.00184

Asia WGS AF: 0.00233 AC: 8 AN: 3452

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.56

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs574142144; hg19: chr7-91866950;