ENST00000486447.1:n.608+85G>T

Variant names:

• chr2-46617108-G-T
• rs113423551
• ENST00000486447.1:n.608+85G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000486447.1(CRIPT):​n.608+85G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.111 in 843,824 control chromosomes in the GnomAD database, including 7,845 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (3290 hom., cov: 32)
  • Exomes 𝑓: 0.099 (4555 hom.)
• Consequence: CRIPT ENST00000486447.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0690
• Publications: 6 publications found

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]

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)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 2-46617108-G-T is Benign according to our data. Variant chr2-46617108-G-T is described in ClinVar as [Benign]. Clinvar id is 1251822.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.36 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIGF	NM_002643.4	c.-160C>A		upstream_gene_variant		ENST00000281382.11	NP_002634.1
CRIPT	NM_014171.6	c.-175G>T		upstream_gene_variant		ENST00000238892.4	NP_054890.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIGF	ENST00000281382.11	c.-160C>A		upstream_gene_variant		1	NM_002643.4	ENSP00000281382.6
CRIPT	ENST00000238892.4	c.-175G>T		upstream_gene_variant		1	NM_014171.6	ENSP00000238892.3

Frequencies

GnomAD3 genomes AF: 0.163 AC: 24805 AN: 152086 Hom.: 3279 Cov.: 32

Gnomad AFR AF: 0.365

Gnomad AMI AF: 0.0504

Gnomad AMR AF: 0.112

Gnomad ASJ AF: 0.101

Gnomad EAS AF: 0.0392

Gnomad SAS AF: 0.150

Gnomad FIN AF: 0.0468

Gnomad MID AF: 0.149

Gnomad NFE AF: 0.0858

Gnomad OTH AF: 0.133

GnomAD4 exome AF: 0.0992 AC: 68623 AN: 691620 Hom.: 4555 Cov.: 9 AF XY: 0.0998 AC XY: 36189 AN XY: 362546

African (AFR) AF: 0.374 AC: 6865 AN: 18352

American (AMR) AF: 0.0997 AC: 3323 AN: 33340

Ashkenazi Jewish (ASJ) AF: 0.104 AC: 2025 AN: 19456

East Asian (EAS) AF: 0.0467 AC: 1520 AN: 32528

South Asian (SAS) AF: 0.144 AC: 8903 AN: 62040

European-Finnish (FIN) AF: 0.0553 AC: 1884 AN: 34072

Middle Eastern (MID) AF: 0.150 AC: 407 AN: 2716

European-Non Finnish (NFE) AF: 0.0880 AC: 39984 AN: 454136

Other (OTH) AF: 0.106 AC: 3712 AN: 34980

GnomAD4 genome AF: 0.163 AC: 24849 AN: 152204 Hom.: 3290 Cov.: 32 AF XY: 0.158 AC XY: 11725 AN XY: 74432

African (AFR) AF: 0.365 AC: 15154 AN: 41478

American (AMR) AF: 0.112 AC: 1718 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.101 AC: 352 AN: 3472

East Asian (EAS) AF: 0.0393 AC: 203 AN: 5166

South Asian (SAS) AF: 0.149 AC: 719 AN: 4824

European-Finnish (FIN) AF: 0.0468 AC: 498 AN: 10630

Middle Eastern (MID) AF: 0.156 AC: 46 AN: 294

European-Non Finnish (NFE) AF: 0.0858 AC: 5833 AN: 68012

Other (OTH) AF: 0.133 AC: 280 AN: 2108

Alfa AF: 0.100 Hom.: 283

Bravo AF: 0.177

Asia WGS AF: 0.111 AC: 388 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	7.8
DANN	Benign	0.91
PhyloP100		-0.069
PromoterAI		-0.058	Neutral
Mutation Taster		=300/0	polymorphism (auto)

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: rs113423551; hg19: chr2-46844247;