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.

• 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	Protein	UniProt
IMPG1	NM_001563.4	c.2282G>A	p.Ser761Asn	missense_variant	16/17	ENST00000369950.8	NP_001554.2
IMPG1	NM_001282368.2	c.2048G>A	p.Ser683Asn	missense_variant	15/16		NP_001269297.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IMPG1	ENST00000369950.8	c.2282G>A	p.Ser761Asn	missense_variant	16/17	1	NM_001563.4	ENSP00000358966.3
IMPG1	ENST00000611179.4	c.2048G>A	p.Ser683Asn	missense_variant	15/16	5		ENSP00000481913.1
IMPG1	ENST00000369952.3	c.365G>A	p.Ser122Asn	missense_variant	3/4	3		ENSP00000358968.3

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

Labcorp Genetics (formerly Invitae), Labcorp

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;.;.
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;