rs713993047

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PP3_ModeratePP5

The NM_001563.4(IMPG1):c.461T>C(p.Leu154Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000799 in 1,613,994 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000087 ( 0 hom. )

Consequence

IMPG1
NM_001563.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:1

Conservation

PhyloP100: 8.82

Publications

2 publications found

Variant links:

Genes affected

IMPG1 (HGNC:6055): (interphotoreceptor matrix proteoglycan 1) This gene encodes a protein that is a major component of the retinal interphotoreceptor matrix. The encoded protein is a proteoglycan that is thought to play a role in maintaining viability of photoreceptor cells and in adhesion of the neural retina to the retinal pigment epithelium. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Sep 2013]

IMPG1 Gene-Disease associations (from GenCC):

inherited retinal dystrophy
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
vitelliform macular dystrophy 4
Inheritance: AD, AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Laboratory for Molecular Medicine, ClinGen, G2P, Labcorp Genetics (formerly Invitae)
retinitis pigmentosa
Inheritance: AR, AD Classification: MODERATE Submitted by: Franklin by Genoox
adult-onset foveomacular vitelliform dystrophy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

IMPG1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

PP3

MetaRNN computational evidence supports a deleterious effect, 0.905

PP5

Variant 6-76034628-A-G is Pathogenic according to our data. Variant chr6-76034628-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 162136.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IMPG1	NM_001563.4 link	c.461T>C	p.Leu154Pro	missense_variant	Exon 3 of 17	ENST00000369950.8	NP_001554.2	Q17R60-1
IMPG1	NM_001282368.2 link	c.227T>C	p.Leu76Pro	missense_variant	Exon 2 of 16		NP_001269297.1	Q17R60A0A087WYL3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
IMPG1	ENST00000369950.8 link	c.461T>C	p.Leu154Pro	missense_variant	Exon 3 of 17	1	NM_001563.4	ENSP00000358966.3	Q17R60-1
IMPG1	ENST00000611179.4 link	c.227T>C	p.Leu76Pro	missense_variant	Exon 2 of 16	5		ENSP00000481913.1	A0A087WYL3
IMPG1	ENST00000369963.5 link	c.206T>C	p.Leu69Pro	missense_variant	Exon 3 of 6	5		ENSP00000358980.4	A0A0R4J2E9

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000358

AC:

AN:

251240

AF XY:

0.0000516

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:

0.0000792

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000869

AC:

127

AN:

1461810

Hom.:

Cov.:

AF XY:

0.0000921

AC XY:

AN XY:

727216

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000112

AC:

125

AN:

1111944

Other (OTH)

AF:

0.0000331

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152184

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74344

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41446

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68036

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000226

Hom.:

Bravo

AF:

0.0000416

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Vitelliform macular dystrophy 4

Pathogenic:1

Sep 05, 2013

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Retinal dystrophy

Pathogenic:1

Jun 14, 2017

Blueprint Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:1

Nov 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 154 of the IMPG1 protein (p.Leu154Pro). This variant is present in population databases (rs713993047, gnomAD 0.008%). This missense change has been observed in individual(s) with vitelliform macular dystrophy and/or retinitis pigmentosa (PMID: 23993198, 30688845; internal data). ClinVar contains an entry for this variant (Variation ID: 162136). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.88

BayesDel_addAF

Benign

-0.079

BayesDel_noAF

Benign

-0.16

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.088

T;.;T

Eigen

Pathogenic

0.72

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Benign

0.82

T;T;T

M_CAP

Pathogenic

0.52

MetaRNN

Pathogenic

0.90

D;D;D

MetaSVM

Uncertain

0.12

MutationAssessor

Uncertain

2.7

M;.;.

PhyloP100

8.8

PrimateAI

Uncertain

0.61

PROVEAN

Pathogenic

-4.8

D;.;.

REVEL

Uncertain

0.52

Sift

Uncertain

0.0020

D;.;.

Sift4G

Uncertain

0.0020

D;D;D

Polyphen

1.0

D;.;.

Vest4

0.94

MVP

0.43

MPC

0.10

ClinPred

0.95

GERP RS

5.0

Varity_R

0.88

gMVP

0.84

Mutation Taster

=12/88

disease causing (ClinVar)

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over