chr6-75922133-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_001563.4(IMPG1):​c.2350G>A​(p.Val784Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000738 in 1,410,134 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000070 ( 0 hom. )

Consequence

IMPG1
NM_001563.4 missense

Scores

19

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: -1.29
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.016674668).
BP6
Variant 6-75922133-C-T is Benign according to our data. Variant chr6-75922133-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 946530.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
IMPG1NM_001563.4 linkuse as main transcriptc.2350G>A p.Val784Ile missense_variant 17/17 ENST00000369950.8
IMPG1NM_001282368.2 linkuse as main transcriptc.2116G>A p.Val706Ile missense_variant 16/16

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
IMPG1ENST00000369950.8 linkuse as main transcriptc.2350G>A p.Val784Ile missense_variant 17/171 NM_001563.4 P2Q17R60-1
IMPG1ENST00000611179.4 linkuse as main transcriptc.2116G>A p.Val706Ile missense_variant 16/165 A2
IMPG1ENST00000369952.3 linkuse as main transcriptc.433G>A p.Val145Ile missense_variant 4/43

Frequencies

GnomAD3 genomes
AF:
0.000105
AC:
16
AN:
152082
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000121
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000328
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000588
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000808
AC:
17
AN:
210434
Hom.:
0
AF XY:
0.0000711
AC XY:
8
AN XY:
112588
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000304
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000247
Gnomad SAS exome
AF:
0.0000763
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000222
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000700
AC:
88
AN:
1257934
Hom.:
0
Cov.:
19
AF XY:
0.0000680
AC XY:
43
AN XY:
632242
show subpopulations
Gnomad4 AFR exome
AF:
0.000135
Gnomad4 AMR exome
AF:
0.000298
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000105
Gnomad4 SAS exome
AF:
0.0000889
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000619
Gnomad4 OTH exome
AF:
0.0000565
GnomAD4 genome
AF:
0.000105
AC:
16
AN:
152200
Hom.:
0
Cov.:
32
AF XY:
0.000134
AC XY:
10
AN XY:
74426
show subpopulations
Gnomad4 AFR
AF:
0.000120
Gnomad4 AMR
AF:
0.000327
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.000208
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000588
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000574
Hom.:
0
Bravo
AF:
0.0000756
ExAC
AF:
0.0000332
AC:
4

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInvitaeJan 25, 2024This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 784 of the IMPG1 protein (p.Val784Ile). This variant is present in population databases (rs576579238, gnomAD 0.04%). 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: 946530). 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. -
not specified Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsNov 15, 2021This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.079
BayesDel_addAF
Benign
-0.62
T
BayesDel_noAF
Benign
-0.82
CADD
Benign
0.051
DANN
Benign
0.46
DEOGEN2
Benign
0.00041
T;.;.
Eigen
Benign
-2.1
Eigen_PC
Benign
-2.1
FATHMM_MKL
Benign
0.0097
N
LIST_S2
Benign
0.42
T;T;T
M_CAP
Benign
0.0041
T
MetaRNN
Benign
0.017
T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.77
N;.;.
MutationTaster
Benign
1.0
N;N
PrimateAI
Benign
0.27
T
PROVEAN
Benign
-0.38
N;.;N
REVEL
Benign
0.0030
Sift
Benign
0.87
T;.;T
Sift4G
Benign
0.98
T;T;T
Polyphen
0.0
B;.;.
Vest4
0.048
MVP
0.072
MPC
0.013
ClinPred
0.015
T
GERP RS
-8.0
Varity_R
0.019
gMVP
0.066

Splicing

Name
Calibrated prediction
Score
Prediction
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: rs576579238; hg19: chr6-76631850; API