Genetic Variant IPP:p.Arg576His (chr1-45699994-C-T) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_005897.3(IPP):c.1727G>A(p.Arg576His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,614,074 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: 𝑓 0.0000066 ( 0 hom., cov: 32)

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: 7.29

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.96

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IPP	NM_005897.3 link	c.1727G>A	p.Arg576His	missense_variant	Exon 9 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.1727G>A	p.Arg576His	missense_variant	Exon 9 of 9	2	NM_005897.3	ENSP00000379739.3	Q9Y573-1
IPP	ENST00000359942.8 link	c.1651+76G>A		intron_variant	Intron 9 of 9	1		ENSP00000353024.4	Q9Y573-2
IPP	ENST00000495072.1 link	n.204G>A		non_coding_transcript_exon_variant	Exon 2 of 3	5

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251442

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135900

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461880

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727244

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

AF:

0.00000657

AC:

AN:

152194

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 06, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1727G>A (p.R576H) alteration is located in exon 9 (coding exon 8) of the IPP gene. This alteration results from a G to A substitution at nucleotide position 1727, causing the arginine (R) at amino acid position 576 to be replaced by a histidine (H). 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

Pathogenic

0.86

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.34

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.46

Eigen

Pathogenic

0.82

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.94

M_CAP

Uncertain

0.26

MetaRNN

Pathogenic

0.96

MetaSVM

Uncertain

0.37

MutationAssessor

Uncertain

2.7

PrimateAI

Uncertain

0.74

PROVEAN

Uncertain

-4.1

REVEL

Pathogenic

0.75

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0030

Polyphen

1.0

Vest4

0.83

MutPred

0.87

Gain of disorder (P = 0.1272);

MVP

0.95

MPC

0.71

ClinPred

1.0

GERP RS

6.1

Varity_R

0.64

gMVP

0.87

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over