6-75922166-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001563.4(IMPG1):​c.2317G>A​(p.Val773Ile) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 152,092 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000018 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

IMPG1
NM_001563.4 missense, splice_region

Scores

19
Splicing: ADA: 0.004762
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.465
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.05224389).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
IMPG1NM_001563.4 linkuse as main transcriptc.2317G>A p.Val773Ile missense_variant, splice_region_variant 17/17 ENST00000369950.8
IMPG1NM_001282368.2 linkuse as main transcriptc.2083G>A p.Val695Ile missense_variant, splice_region_variant 16/16

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
IMPG1ENST00000369950.8 linkuse as main transcriptc.2317G>A p.Val773Ile missense_variant, splice_region_variant 17/171 NM_001563.4 P2Q17R60-1
IMPG1ENST00000611179.4 linkuse as main transcriptc.2083G>A p.Val695Ile missense_variant, splice_region_variant 16/165 A2
IMPG1ENST00000369952.3 linkuse as main transcriptc.400G>A p.Val134Ile missense_variant, splice_region_variant 4/43

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152092
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
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:
0.00000529
AC:
1
AN:
189208
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
100830
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000377
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:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
AF:
0.00000179
AC:
2
AN:
1116162
Hom.:
0
Cov.:
15
AF XY:
0.00000177
AC XY:
1
AN XY:
565716
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000264
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000272
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152092
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74292
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000131
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:
0.0000113

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInvitaeOct 22, 2023This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 773 of the IMPG1 protein (p.Val773Ile). This variant is present in population databases (no rsID available, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with IMPG1-related conditions. ClinVar contains an entry for this variant (Variation ID: 2001168). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The isoleucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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
Benign
0.078
BayesDel_addAF
Benign
-0.42
T
BayesDel_noAF
Benign
-0.72
CADD
Benign
15
DANN
Benign
0.94
DEOGEN2
Benign
0.00042
T;.;.
Eigen
Benign
-0.51
Eigen_PC
Benign
-0.35
FATHMM_MKL
Benign
0.62
D
LIST_S2
Benign
0.62
T;T;T
M_CAP
Benign
0.0051
T
MetaRNN
Benign
0.052
T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.030
N;.;.
MutationTaster
Benign
1.0
D;N
PrimateAI
Benign
0.36
T
PROVEAN
Benign
-0.14
N;.;N
REVEL
Benign
0.011
Sift
Benign
0.25
T;.;T
Sift4G
Benign
0.29
T;T;T
Polyphen
0.0020
B;.;.
Vest4
0.058
MutPred
0.27
Gain of catalytic residue at V773 (P = 0.0258);.;.;
MVP
0.19
MPC
0.013
ClinPred
0.049
T
GERP RS
3.1
Varity_R
0.035
gMVP
0.16

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.0048
dbscSNV1_RF
Benign
0.17
SpliceAI score (max)
0.020
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.

Other links and lift over

dbSNP: rs1449114259; hg19: chr6-76631883; API