rs137853139

chr7-92236488-T-Achr7-92236488-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PM5 PP3_Moderate

The NM_194454.3(KRIT1):c.410A>T(p.Asp137Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,114 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D137G) has been classified as Likely pathogenic.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: KRIT1 NM_194454.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.51

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-92236488-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 5725.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.899

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KRIT1	NM_194454.3	c.410A>T	p.Asp137Val	missense_variant	7/19	ENST00000394505.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KRIT1	ENST00000394505.7	c.410A>T	p.Asp137Val	missense_variant	7/19	1	NM_194454.3	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152114 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 26

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152114 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74300

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.40
Cadd	Pathogenic	27
Dann	Uncertain	0.99
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;D;.;.;.;D;D;D;D
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.90	D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.59	D
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.77	T
Polyphen		1.0	.;D;D;D;D;.;.;.;.
Vest4		0.93, 0.94, 0.97, 0.94, 0.95
MutPred		0.75		Gain of helix (P = 0.1736);Gain of helix (P = 0.1736);Gain of helix (P = 0.1736);Gain of helix (P = 0.1736);Gain of helix (P = 0.1736);Gain of helix (P = 0.1736);Gain of helix (P = 0.1736);Gain of helix (P = 0.1736);Gain of helix (P = 0.1736);
MVP		0.95
MPC		1.2
ClinPred		0.94	D
GERP RS		5.2
Varity_R		0.46
gMVP		0.83

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

Publications

LitVar

Other links and lift over

dbSNP: rs137853139; hg19: chr7-91865802;