NM_001563.4:c.2305C>G

Variant names:

• chr6-75923645-G-C
• rs746517520
• NM_001563.4:c.2305C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001563.4(IMPG1):​c.2305C>G​(p.Gln769Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000129 in 1,544,702 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: IMPG1 NM_001563.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.721
• Publications: 0 publications found

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):

• IMPG1-related dominant retinopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• vitelliform macular dystrophy 4

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P
• IMPG1-related recessive retinopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• retinitis pigmentosa

  Inheritance: AR, AD Classification: MODERATE Submitted by: Franklin by Genoox
• adult-onset foveomacular vitelliform dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1665099).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001563.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IMPG1	NM_001563.4	MANE Select	c.2305C>G	p.Gln769Glu	missense	Exon 16 of 17	NP_001554.2
	IMPG1	NM_001282368.2		c.2071C>G	p.Gln691Glu	missense	Exon 15 of 16	NP_001269297.1	A0A087WYL3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IMPG1	ENST00000369950.8	TSL:1 MANE Select	c.2305C>G	p.Gln769Glu	missense	Exon 16 of 17	ENSP00000358966.3	Q17R60-1
	IMPG1	ENST00000611179.4	TSL:5	c.2071C>G	p.Gln691Glu	missense	Exon 15 of 16	ENSP00000481913.1	A0A087WYL3
	IMPG1	ENST00000369952.3	TSL:3	c.388C>G	p.Gln130Glu	missense	Exon 3 of 4	ENSP00000358968.3	Q5JSC4

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152098 Hom.: 0 Cov.: 32

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 7.18e-7 AC: 1 AN: 1392604 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 696190

African (AFR) AF: 0.00 AC: 0 AN: 32498

American (AMR) AF: 0.00 AC: 0 AN: 43620

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25630

East Asian (EAS) AF: 0.00 AC: 0 AN: 39318

South Asian (SAS) AF: 0.00 AC: 0 AN: 83936

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52932

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5638

European-Non Finnish (NFE) AF: 9.52e-7 AC: 1 AN: 1050888

Other (OTH) AF: 0.00 AC: 0 AN: 58144

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152098 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74288

African (AFR) AF: 0.00 AC: 0 AN: 41444

American (AMR) AF: 0.00 AC: 0 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67960

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0011	T
Eigen	Benign	0.16
Eigen_PC	Benign	0.19
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.0093	T
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	2.0	M
PhyloP100		0.72
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.73	N
REVEL	Benign	0.025
Sift	Uncertain	0.0090	D
Sift4G	Benign	0.081	T
Polyphen		0.78	P
Vest4		0.18
MutPred		0.22		Gain of sheet (P = 0.0061)
MVP		0.45
MPC		0.015
ClinPred		0.54	D
GERP RS		4.0
Varity_R		0.15
gMVP		0.49
Mutation Taster		=75/25	polymorphism

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

Other links and lift over

dbSNP: rs746517520; hg19: chr6-76633362;