Genetic Variant IPP:p.Leu468Phe (chr1-45714374-G-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_005897.3(IPP):c.1402C>T(p.Leu468Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,556 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

IPP
NM_005897.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.03

Variant links:

Genes affected

IPP (HGNC:6108): (intracisternal A particle-promoted polypeptide) The protein encoded by this gene is a member of the kelch family of proteins, which is characterized by a 50 amino acid repeat which interacts with actin. Transcript variants have been described but their full-length nature has not been determined. [provided by RefSeq, Jul 2008]

IPP links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.841

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IPP	NM_005897.3 link	c.1402C>T	p.Leu468Phe	missense_variant	Exon 8 of 9	ENST00000396478.4	NP_005888.1	Q9Y573-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
IPP	ENST00000396478.4 link	c.1402C>T	p.Leu468Phe	missense_variant	Exon 8 of 9	2	NM_005897.3	ENSP00000379739.3	Q9Y573-1
IPP	ENST00000359942.8 link	c.1402C>T	p.Leu468Phe	missense_variant	Exon 8 of 10	1		ENSP00000353024.4	Q9Y573-2
IPP	ENST00000495072.1 link	n.-122C>T		upstream_gene_variant		5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461556

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727122

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 28, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1402C>T (p.L468F) alteration is located in exon 8 (coding exon 7) of the IPP gene. This alteration results from a C to T substitution at nucleotide position 1402, causing the leucine (L) at amino acid position 468 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Uncertain

-0.050

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.60

.;D

Eigen

Pathogenic

0.78

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.89

D;D

M_CAP

Uncertain

0.12

MetaRNN

Pathogenic

0.84

D;D

MetaSVM

Uncertain

0.47

MutationAssessor

Uncertain

2.8

M;M

PrimateAI

Uncertain

0.60

PROVEAN

Uncertain

-3.0

D;D

REVEL

Pathogenic

0.72

Sift

Uncertain

0.0040

D;D

Sift4G

Uncertain

0.0090

D;D

Polyphen

1.0

.;D

Vest4

0.70

MutPred

0.64

Loss of glycosylation at P467 (P = 0.0729);Loss of glycosylation at P467 (P = 0.0729);

MVP

0.94

MPC

0.67

ClinPred

0.99

GERP RS

4.9

Varity_R

0.38

gMVP

0.59

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.33

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.33

Position offset: -20

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

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over