rs762278033

Variant names:

• chr6-75922159-C-G
• rs762278033
• NM_001563.4:c.2324G>C

Your query was ambiguous. Multiple possible variants found:

• chr6-75922159-C-G
• chr6-75922159-C-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001563.4(IMPG1):​c.2324G>C​(p.Ser775Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000868 in 1,151,756 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S775N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 8.7e-7 (0 hom.)
• Consequence: IMPG1 NM_001563.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.492
• 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: G2P, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.044150263).

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.2324G>C	p.Ser775Thr	missense	Exon 17 of 17	NP_001554.2
	IMPG1	NM_001282368.2		c.2090G>C	p.Ser697Thr	missense	Exon 16 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.2324G>C	p.Ser775Thr	missense	Exon 17 of 17	ENSP00000358966.3	Q17R60-1
	IMPG1	ENST00000611179.4	TSL:5	c.2090G>C	p.Ser697Thr	missense	Exon 16 of 16	ENSP00000481913.1	A0A087WYL3
	IMPG1	ENST00000369952.3	TSL:3	c.407G>C	p.Ser136Thr	missense	Exon 4 of 4	ENSP00000358968.3	Q5JSC4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 8.68e-7 AC: 1 AN: 1151756 Hom.: 0 Cov.: 16 AF XY: 0.00 AC XY: 0 AN XY: 582360

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 27544

American (AMR) AF: 0.00 AC: 0 AN: 38476

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23660

East Asian (EAS) AF: 0.00 AC: 0 AN: 37114

South Asian (SAS) AF: 0.00 AC: 0 AN: 75902

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50236

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4988

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 844326

Other (OTH) AF: 0.0000202 AC: 1 AN: 49510

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	14
DANN	Benign	0.83
DEOGEN2	Benign	0.00043	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.052	N
LIST_S2	Benign	0.56	T
M_CAP	Benign	0.0025	T
MetaRNN	Benign	0.044	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.49
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.070	N
REVEL	Benign	0.021
Sift	Benign	0.047	D
Sift4G	Benign	0.41	T
Polyphen		0.016	B
Vest4		0.071
MutPred		0.26		Loss of ubiquitination at K776 (P = 0.0504)
MVP		0.24
MPC		0.014
ClinPred		0.043	T
GERP RS		-3.4
Varity_R		0.059
gMVP		0.29
Mutation Taster		=99/1	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: rs762278033; hg19: chr6-76631876;