chr6-75923656-A-G

Position:

chr6-75923656-A-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBS1_Supporting

The NM_001563.4(IMPG1):c.2294T>C(p.Phe765Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000244 in 1,584,654 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F765V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00026 ( 1 hom. )

Consequence

IMPG1
NM_001563.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.50

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.06668651).

BS1

Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.00026 (372/1432504) while in subpopulation NFE AF= 0.000333 (362/1087038). AF 95% confidence interval is 0.000305. There are 1 homozygotes in gnomad4_exome. There are 178 alleles in male gnomad4_exome subpopulation. Median coverage is 25. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IMPG1	NM_001563.4 linkuse as main transcript	c.2294T>C	p.Phe765Ser	missense_variant	16/17	ENST00000369950.8
IMPG1	NM_001282368.2 linkuse as main transcript	c.2060T>C	p.Phe687Ser	missense_variant	15/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IMPG1	ENST00000369950.8 linkuse as main transcript	c.2294T>C	p.Phe765Ser	missense_variant	16/17	1	NM_001563.4	P2	Q17R60-1
IMPG1	ENST00000611179.4 linkuse as main transcript	c.2060T>C	p.Phe687Ser	missense_variant	15/16	5		A2
IMPG1	ENST00000369952.3 linkuse as main transcript	c.377T>C	p.Phe126Ser	missense_variant	3/4	3

Frequencies

GnomAD3 genomes

AF:

0.0000986

AC:

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

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:

0.000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000819

AC:

AN:

244130

Hom.:

AF XY:

0.000106

AC XY:

AN XY:

131832

show subpopulations

Gnomad AFR exome

AF:

0.0000627

Gnomad AMR exome

AF:

0.0000893

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:

0.000137

Gnomad OTH exome

AF:

0.000168

GnomAD4 exome

AF:

0.000260

AC:

372

AN:

1432504

Hom.:

Cov.:

AF XY:

0.000249

AC XY:

178

AN XY:

714008

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000910

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:

0.000333

Gnomad4 OTH exome

AF:

0.000101

GnomAD4 genome

AF:

0.0000986

AC:

AN:

152150

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74332

show subpopulations

Gnomad4 AFR

AF:

0.0000724

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:

0.000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000661

Hom.:

Bravo

AF:

0.000125

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 03, 2023

This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 765 of the IMPG1 protein (p.Phe765Ser). This variant is present in population databases (rs771927192, gnomAD 0.02%). This missense change has been observed in individual(s) with IMPG1-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 838276). 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 serine 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

0.12

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.32

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.0059

T;.;.

Eigen

Benign

-0.58

Eigen_PC

Benign

-0.57

FATHMM_MKL

Benign

0.053

LIST_S2

Benign

0.51

T;T;T

M_CAP

Benign

0.021

MetaRNN

Benign

0.067

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.8

L;.;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.40

PROVEAN

Uncertain

-3.1

D;.;D

REVEL

Benign

0.14

Sift

Uncertain

0.0040

D;.;D

Sift4G

Uncertain

0.015

D;D;D

Polyphen

0.063

B;.;.

Vest4

0.27

MVP

0.13

MPC

0.018

ClinPred

0.073

GERP RS

4.0

Varity_R

0.41

gMVP

0.62

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over