chr2-46617285-GGT-G

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1_StrongPM2PP5_Moderate

The NM_014171.6(CRIPT):c.7_8delTG(p.Cys3ArgfsTer4) variant causes a frameshift change. The variant allele was found at a frequency of 0.000000713 in 1,402,964 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

CRIPT
NM_014171.6 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 5.03

Publications

1 publications found

Variant links:

Genes affected

CRIPT (HGNC:14312): (CXXC repeat containing interactor of PDZ3 domain) This gene encodes a protein that binds to the PDZ3 peptide recognition domain. The encoded protein may modulates protein interactions with the cytoskeleton. A mutation in this gene resulted in short stature with microcephaly and distinctive facies. [provided by RefSeq, Jun 2014]

CRIPT links:

PIGF (HGNC:8962): (phosphatidylinositol glycan anchor biosynthesis class F) This gene encodes a protein involved in glycosylphosphatidylinositol (GPI)-anchor biosynthesis. The GPI-anchor, a glycolipid containing three mannose molecules in its core backbone, is found on many blood cells where it serves to anchor proteins to the cell surface. The encoded protein and another GPI synthesis protein, PIGO, function in the transfer of ethanolaminephosphate to the third mannose in GPI. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

PIGF Gene-Disease associations (from GenCC):

onychodystrophy, osteodystrophy, impaired intellectual development, and seizures syndrome
Inheritance: AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

PIGF links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 8 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 2-46617285-GGT-G is Pathogenic according to our data. Variant chr2-46617285-GGT-G is described in ClinVar as [Pathogenic]. Clinvar id is 1343340.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRIPT	NM_014171.6 link	c.7_8delTG	p.Cys3ArgfsTer4	frameshift_variant	Exon 1 of 5	ENST00000238892.4	NP_054890.1	Q9P021
PIGF	NM_002643.4 link	c.-339_-338delAC		upstream_gene_variant		ENST00000281382.11	NP_002634.1	Q07326-1Q6IB04

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRIPT	ENST00000238892.4 link	c.7_8delTG	p.Cys3ArgfsTer4	frameshift_variant	Exon 1 of 5	1	NM_014171.6	ENSP00000238892.3		Q9P021
PIGF	ENST00000281382.11 link	c.-339_-338delAC		upstream_gene_variant		1	NM_002643.4	ENSP00000281382.6		Q07326-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000630

AC:

AN:

158696

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000165

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

7.13e-7

AC:

AN:

1402964

Hom.:

AF XY:

0.00000144

AC XY:

AN XY:

692114

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32192

American (AMR)

AF:

0.00

AC:

AN:

35780

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25184

East Asian (EAS)

AF:

0.00

AC:

AN:

36768

South Asian (SAS)

AF:

0.00

AC:

AN:

79612

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49170

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5668

European-Non Finnish (NFE)

AF:

9.26e-7

AC:

AN:

1080432

Other (OTH)

AF:

0.00

AC:

AN:

58158

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Rothmund-Thomson syndrome, type 3

Pathogenic:2

Apr 29, 2024

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Mar 09, 2022

Hacettepe Pediatric Genetics Laboratory, Hacettepe University

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Sequencing analysis of the CRIPT gene identified a novel homozygous frameshift variant (c.7_8delTG; p.Cys3Argfs*4) in a patient whose clinical features were compatible with Short Stature with Microcephaly and Distinctive Facies. This variant has not been reported in 1000 Genomes Project database and there is only one heterozygous individual in gnomAD data (allele frequency= 0.0000063). This change was classified as “pathogenic” according to the ACMG guidelines. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

5.0

Mutation Taster

=6/194

disease causing (fs/PTC)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over