6-75922166-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_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: Splicing: ADA: 0.004762
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.465

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]

ACMG classification

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
IMPG1	NM_001563.4	c.2317G>A	p.Val773Ile	missense_variant, splice_region_variant	17/17	ENST00000369950.8
IMPG1	NM_001282368.2	c.2083G>A	p.Val695Ile	missense_variant, splice_region_variant	16/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IMPG1	ENST00000369950.8	c.2317G>A	p.Val773Ile	missense_variant, splice_region_variant	17/17	1	NM_001563.4	P2
IMPG1	ENST00000611179.4	c.2083G>A	p.Val695Ile	missense_variant, splice_region_variant	16/16	5		A2
IMPG1	ENST00000369952.3	c.400G>A	p.Val134Ile	missense_variant, splice_region_variant	4/4	3

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152092 Hom.: 0 Cov.: 32

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

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

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

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

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 22, 2023

This 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

Other links and lift over

dbSNP: rs1449114259; hg19: chr6-76631883;