chr7-92200405-C-T

Variant names:

• chr7-92200405-C-T
• rs888560477
• NM_194454.3:c.*331G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_194454.3(KRIT1):​c.*331G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000795 in 289,438 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000043 (0 hom.)
• Consequence: KRIT1 NM_194454.3 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: -1.57
• 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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• famililal cerebral cavernous malformations

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000289027 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.02).
• BS2: High AC in GnomAd4 at 17 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_194454.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRIT1	NM_194454.3	MANE Select	c.*331G>A		3_prime_UTR	Exon 19 of 19	NP_919436.1	O00522-1
	KRIT1	NM_001350672.1		c.*331G>A		3_prime_UTR	Exon 17 of 17	NP_001337601.1	O00522-1
	KRIT1	NM_001350673.1		c.*331G>A		3_prime_UTR	Exon 18 of 18	NP_001337602.1	O00522-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRIT1	ENST00000394505.7	TSL:1 MANE Select	c.*331G>A		3_prime_UTR	Exon 19 of 19	ENSP00000378013.2	O00522-1
	KRIT1	ENST00000340022.6	TSL:1	c.*331G>A		3_prime_UTR	Exon 19 of 19	ENSP00000344668.2	O00522-1
	KRIT1	ENST00000412043.6	TSL:1	c.*331G>A		3_prime_UTR	Exon 19 of 19	ENSP00000410909.2	O00522-1

Frequencies

GnomAD3 genomes AF: 0.000114 AC: 17 AN: 149282 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000335

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000205

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000133

Gnomad OTH AF: 0.000485

GnomAD4 exome AF: 0.0000428 AC: 6 AN: 140156 Hom.: 0 Cov.: 0 AF XY: 0.0000539 AC XY: 4 AN XY: 74188

African (AFR) AF: 0.000222 AC: 1 AN: 4502

American (AMR) AF: 0.000303 AC: 2 AN: 6594

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3686

East Asian (EAS) AF: 0.00 AC: 0 AN: 7328

South Asian (SAS) AF: 0.0000486 AC: 1 AN: 20590

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6492

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 578

European-Non Finnish (NFE) AF: 0.0000242 AC: 2 AN: 82730

Other (OTH) AF: 0.00 AC: 0 AN: 7656

GnomAD4 genome AF: 0.000114 AC: 17 AN: 149282 Hom.: 0 Cov.: 31 AF XY: 0.0000552 AC XY: 4 AN XY: 72482

African (AFR) AF: 0.00 AC: 0 AN: 40430

American (AMR) AF: 0.000335 AC: 5 AN: 14906

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3454

East Asian (EAS) AF: 0.00 AC: 0 AN: 5110

South Asian (SAS) AF: 0.00 AC: 0 AN: 4746

European-Finnish (FIN) AF: 0.000205 AC: 2 AN: 9736

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.000133 AC: 9 AN: 67620

Other (OTH) AF: 0.000485 AC: 1 AN: 2060

Alfa AF: 0.000285 Hom.: 0

Bravo AF: 0.0000907

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Angiokeratoma corporis diffusum with arteriovenous fistulas (1)
-	1	-	Cerebral cavernous malformation (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.97
DANN	Benign	0.47
PhyloP100		-1.6

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs888560477; hg19: chr7-91829719;