Genetic Variant IPP:p.Arg409Gln (chr1-45716978-C-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_005897.3(IPP):c.1226G>A(p.Arg409Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,460,790 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. R409L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

IPP
NM_005897.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.63

Publications

3 publications found

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 was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.82

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005897.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IPP	NM_005897.3	MANE Select	c.1226G>A	p.Arg409Gln	missense	Exon 7 of 9	NP_005888.1	Q9Y573-1
	IPP	NM_001145349.2		c.1226G>A	p.Arg409Gln	missense	Exon 7 of 10	NP_001138821.1	Q9Y573-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IPP	ENST00000396478.4	TSL:2 MANE Select	c.1226G>A	p.Arg409Gln	missense	Exon 7 of 9	ENSP00000379739.3	Q9Y573-1
IPP	ENST00000359942.8	TSL:1	c.1226G>A	p.Arg409Gln	missense	Exon 7 of 10	ENSP00000353024.4	Q9Y573-2
IPP	ENST00000890995.1		c.1226G>A	p.Arg409Gln	missense	Exon 8 of 10	ENSP00000561054.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251120

AF XY:

0.00000737

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:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1460790

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726754

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33468

American (AMR)

AF:

0.00

AC:

AN:

44662

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39634

South Asian (SAS)

AF:

0.00

AC:

AN:

86164

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53410

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111212

Other (OTH)

AF:

0.00

AC:

AN:

60354

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0385499), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000244

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.25

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.41

Eigen

Pathogenic

0.69

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.89

M_CAP

Uncertain

0.10

MetaRNN

Pathogenic

0.82

MetaSVM

Uncertain

0.49

MutationAssessor

Uncertain

2.4

PhyloP100

5.6

PrimateAI

Benign

0.47

PROVEAN

Uncertain

-2.4

REVEL

Pathogenic

0.78

Sift

Benign

0.34

Sift4G

Benign

0.27

Polyphen

0.99

Vest4

0.64

MutPred

0.54

Loss of phosphorylation at T406 (P = 0.1411)

MVP

0.91

MPC

0.68

ClinPred

0.96

GERP RS

4.7

Varity_R

0.24

gMVP

0.69

Mutation Taster

=72/28

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over