rs713993045

Variant names:

• chr6-76018812-A-C
• rs713993045
• NM_001563.4:c.713T>G

Your query was ambiguous. Multiple possible variants found:

• chr6-76018812-A-C
• chr6-76018812-A-G

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PM5 PP3_Moderate PP5

The NM_001563.4(IMPG1):​c.713T>G​(p.Leu238Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L238P) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: IMPG1 NM_001563.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.37
• Publications: 3 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):

• inherited retinal dystrophy

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

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Laboratory for Molecular Medicine, ClinGen, G2P, Labcorp Genetics (formerly Invitae)
• 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: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr6-76018812-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 865770.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.883
• PP5: Variant 6-76018812-A-C is Pathogenic according to our data. Variant chr6-76018812-A-C is described in ClinVar as Pathogenic. ClinVar VariationId is 162133.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IMPG1	NM_001563.4	c.713T>G	p.Leu238Arg	missense_variant	Exon 7 of 17	ENST00000369950.8	NP_001554.2
IMPG1	NM_001282368.2	c.479T>G	p.Leu160Arg	missense_variant	Exon 6 of 16		NP_001269297.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IMPG1	ENST00000369950.8	c.713T>G	p.Leu238Arg	missense_variant	Exon 7 of 17	1	NM_001563.4	ENSP00000358966.3
IMPG1	ENST00000611179.4	c.479T>G	p.Leu160Arg	missense_variant	Exon 6 of 16	5		ENSP00000481913.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Vitelliform macular dystrophy 4 Pathogenic:1

Sep 05, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Uncertain	0.030	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.038	T;.
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.86	D;D
M_CAP	Benign	0.033	D
MetaRNN	Pathogenic	0.88	D;D
MetaSVM	Benign	-0.86	T
MutationAssessor	Uncertain	2.4	M;.
PhyloP100		5.4
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-2.8	D;.
REVEL	Uncertain	0.34
Sift	Uncertain	0.0010	D;.
Sift4G	Uncertain	0.0030	D;D
Polyphen		0.99	D;.
Vest4		0.84
MutPred		0.67		Gain of MoRF binding (P = 0.0217);.;
MVP		0.74
MPC		0.099
ClinPred		0.98	D
GERP RS		6.1
Varity_R		0.67
gMVP		0.73
Mutation Taster		=26/74	disease causing (ClinVar)

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: rs713993045; hg19: chr6-76728529; COSMIC: COSV105286382;