6-75923668-C-T

Position:

• chr6-75923668-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001563.4(IMPG1):​c.2282G>A​(p.Ser761Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.234 in 1,582,566 control chromosomes in the GnomAD database, including 47,346 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Synonymous variant affecting the same amino acid position (i.e. S761S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.18 (3225 hom., cov: 32)
  • Exomes 𝑓: 0.24 (44121 hom.)
• Consequence: IMPG1 NM_001563.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0960

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013806224).
• BP6: Variant 6-75923668-C-T is Benign according to our data. Variant chr6-75923668-C-T is described in ClinVar as [Benign]. Clinvar id is 1164207.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-75923668-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.266 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IMPG1	NM_001563.4	c.2282G>A	p.Ser761Asn	missense_variant	16/17	ENST00000369950.8
IMPG1	NM_001282368.2	c.2048G>A	p.Ser683Asn	missense_variant	15/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IMPG1	ENST00000369950.8	c.2282G>A	p.Ser761Asn	missense_variant	16/17	1	NM_001563.4	P2
IMPG1	ENST00000611179.4	c.2048G>A	p.Ser683Asn	missense_variant	15/16	5		A2
IMPG1	ENST00000369952.3	c.365G>A	p.Ser122Asn	missense_variant	3/4	3

Frequencies

GnomAD3 genomes AF: 0.185 AC: 28037 AN: 151950 Hom.: 3222 Cov.: 32

Gnomad AFR AF: 0.0614

Gnomad AMI AF: 0.161

Gnomad AMR AF: 0.206

Gnomad ASJ AF: 0.176

Gnomad EAS AF: 0.0494

Gnomad SAS AF: 0.148

Gnomad FIN AF: 0.176

Gnomad MID AF: 0.218

Gnomad NFE AF: 0.269

Gnomad OTH AF: 0.209

GnomAD3 exomes AF: 0.191 AC: 46441 AN: 243518 Hom.: 5029 AF XY: 0.194 AC XY: 25518 AN XY: 131524

Gnomad AFR exome AF: 0.0551

Gnomad AMR exome AF: 0.174

Gnomad ASJ exome AF: 0.166

Gnomad EAS exome AF: 0.0506

Gnomad SAS exome AF: 0.151

Gnomad FIN exome AF: 0.176

Gnomad NFE exome AF: 0.253

Gnomad OTH exome AF: 0.224

GnomAD4 exome AF: 0.239 AC: 342209 AN: 1430498 Hom.: 44121 Cov.: 26 AF XY: 0.238 AC XY: 169443 AN XY: 712744

Gnomad4 AFR exome AF: 0.0552

Gnomad4 AMR exome AF: 0.180

Gnomad4 ASJ exome AF: 0.170

Gnomad4 EAS exome AF: 0.0507

Gnomad4 SAS exome AF: 0.155

Gnomad4 FIN exome AF: 0.182

Gnomad4 NFE exome AF: 0.266

Gnomad4 OTH exome AF: 0.220

GnomAD4 genome AF: 0.184 AC: 28045 AN: 152068 Hom.: 3225 Cov.: 32 AF XY: 0.180 AC XY: 13348 AN XY: 74350

Gnomad4 AFR AF: 0.0614

Gnomad4 AMR AF: 0.206

Gnomad4 ASJ AF: 0.176

Gnomad4 EAS AF: 0.0499

Gnomad4 SAS AF: 0.148

Gnomad4 FIN AF: 0.176

Gnomad4 NFE AF: 0.269

Gnomad4 OTH AF: 0.208

Alfa AF: 0.245 Hom.: 7303

Bravo AF: 0.181

TwinsUK AF: 0.274 AC: 1017

ALSPAC AF: 0.276 AC: 1065

ESP6500AA AF: 0.0606 AC: 267

ESP6500EA AF: 0.261 AC: 2239

ExAC AF: 0.191 AC: 23135

Asia WGS AF: 0.0920 AC: 322 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Retinal dystrophy Benign:1

Benign, criteria provided, single submitter

research

Dept Of Ophthalmology, Nagoya University

Oct 01, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.81	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	4.6
DANN	Benign	0.51
DEOGEN2	Benign	0.00035	T;.;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.019	N
LIST_S2	Benign	0.60	T;T;T
MetaRNN	Benign	0.014	T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.2	L;.;.
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.32	N;.;N
REVEL	Benign	0.0090
Sift	Benign	0.97	T;.;T
Sift4G	Benign	0.64	T;T;T
Polyphen		0.0040	B;.;.
Vest4		0.069
MPC		0.013
ClinPred		0.00072	T
GERP RS		0.067
Varity_R		0.032
gMVP		0.24

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

Publications

LitVar

Other links and lift over

dbSNP: rs3778005; hg19: chr6-76633385;