dbSNP rs746369854: IMP3:p.Arg56Leu (chr15-75640002-C-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_018285.4(IMP3):c.167G>T(p.Arg56Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000069 in 1,449,312 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. R56P) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

IMP3
NM_018285.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.40

Variant links:

Genes affected

IMP3 (HGNC:14497): (IMP U3 small nucleolar ribonucleoprotein 3) This gene encodes the human homolog of the yeast Imp3 protein. The protein localizes to the nucleoli and interacts with the U3 snoRNP complex. The protein contains an S4 domain. [provided by RefSeq, Jul 2008]

IMP3 links:

ENSG00000275454 (HGNC:):

ENSG00000275454 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.874

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IMP3	NM_018285.4 link	c.167G>T	p.Arg56Leu	missense_variant	Exon 1 of 1	ENST00000403490.3	NP_060755.1	Q9NV31

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
IMP3	ENST00000403490.3 link	c.167G>T	p.Arg56Leu	missense_variant	Exon 1 of 1	6	NM_018285.4	ENSP00000385217.1	Q9NV31
IMP3	ENST00000314852.2 link	c.167G>T	p.Arg56Leu	missense_variant	Exon 2 of 2	2		ENSP00000326981.2	Q9NV31
ENSG00000275454	ENST00000621523.1 link	n.243C>A		non_coding_transcript_exon_variant	Exon 1 of 1	6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000456

AC:

AN:

219060

AF XY:

0.00000824

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:

0.0000105

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.90e-7

AC:

AN:

1449312

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

720160

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33176

American (AMR)

AF:

0.00

AC:

AN:

43186

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25862

East Asian (EAS)

AF:

0.00

AC:

AN:

39026

South Asian (SAS)

AF:

0.00

AC:

AN:

85154

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50444

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5630

European-Non Finnish (NFE)

AF:

9.03e-7

AC:

AN:

1106972

Other (OTH)

AF:

0.00

AC:

AN:

59862

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000837

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.90

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Uncertain

0.030

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.32

T;T

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

.;D

M_CAP

Pathogenic

0.53

MetaRNN

Pathogenic

0.87

D;D

MetaSVM

Benign

-0.45

MutationAssessor

Uncertain

2.5

M;M

PhyloP100

5.4

PrimateAI

Pathogenic

0.90

PROVEAN

Pathogenic

-5.7

D;D

REVEL

Uncertain

0.35

Sift

Benign

0.040

D;D

Sift4G

Uncertain

0.059

T;T

Polyphen

1.0

D;D

Vest4

0.73

MutPred

0.62

Loss of methylation at R56 (P = 0.0253);Loss of methylation at R56 (P = 0.0253);

MVP

0.79

MPC

1.2

ClinPred

0.99

GERP RS

6.1

PromoterAI

-0.14

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.66

gMVP

0.77

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

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

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