6-75923657-A-C

Position:

• chr6-75923657-A-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001563.4(IMPG1):​c.2293T>G​(p.Phe765Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: IMPG1 NM_001563.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.0860

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=0.046073675).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IMPG1	NM_001563.4	c.2293T>G	p.Phe765Val	missense_variant	16/17	ENST00000369950.8	NP_001554.2
IMPG1	NM_001282368.2	c.2059T>G	p.Phe687Val	missense_variant	15/16		NP_001269297.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IMPG1	ENST00000369950.8	c.2293T>G	p.Phe765Val	missense_variant	16/17	1	NM_001563.4	ENSP00000358966.3
IMPG1	ENST00000611179.4	c.2059T>G	p.Phe687Val	missense_variant	15/16	5		ENSP00000481913.1
IMPG1	ENST00000369952.3	c.376T>G	p.Phe126Val	missense_variant	3/4	3		ENSP00000358968.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1433726 Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 714574

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

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 Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 01, 2023

The c.2293T>G (p.F765V) alteration is located in exon 16 (coding exon 16) of the IMPG1 gene. This alteration results from a T to G substitution at nucleotide position 2293, causing the phenylalanine (F) at amino acid position 765 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 14, 2022

This variant is not present in population databases (gnomAD no frequency). 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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. This variant has not been reported in the literature in individuals affected with IMPG1-related conditions. This sequence change replaces phenylalanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 765 of the IMPG1 protein (p.Phe765Val). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	9.1
DANN	Benign	0.95
DEOGEN2	Benign	0.0029	T;.;.
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.027	N
LIST_S2	Benign	0.59	T;T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.046	T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.8	L;.;.
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-2.7	D;.;D
REVEL	Benign	0.042
Sift	Benign	0.14	T;.;T
Sift4G	Benign	0.10	T;T;D
Polyphen		0.0	B;.;.
Vest4		0.22
MutPred		0.12		Gain of MoRF binding (P = 0.0814);.;.;
MVP		0.067
MPC		0.013
ClinPred		0.14	T
GERP RS		1.6
Varity_R		0.16
gMVP		0.41

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-76633374;