chr6-75950834-G-C

Position:

• chr6-75950834-G-C

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.1552C>G​(p.His518Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.421 in 1,613,124 control chromosomes in the GnomAD database, including 147,619 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 0.46 (16804 hom., cov: 33)
  • Exomes 𝑓: 0.42 (130815 hom.)
• Consequence: IMPG1 NM_001563.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.709

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=2.6915104E-6).
• BP6: Variant 6-75950834-G-C is Benign according to our data. Variant chr6-75950834-G-C is described in ClinVar as [Benign]. Clinvar id is 1165049.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-75950834-G-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.652 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IMPG1	NM_001563.4	c.1552C>G	p.His518Asp	missense_variant	13/17	ENST00000369950.8	NP_001554.2
IMPG1	NM_001282368.2	c.1318C>G	p.His440Asp	missense_variant	12/16		NP_001269297.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IMPG1	ENST00000369950.8	c.1552C>G	p.His518Asp	missense_variant	13/17	1	NM_001563.4	ENSP00000358966.3
IMPG1	ENST00000611179.4	c.1318C>G	p.His440Asp	missense_variant	12/16	5		ENSP00000481913.1

Frequencies

GnomAD3 genomes AF: 0.463 AC: 70434 AN: 151974 Hom.: 16773 Cov.: 33

Gnomad AFR AF: 0.541

Gnomad AMI AF: 0.567

Gnomad AMR AF: 0.520

Gnomad ASJ AF: 0.486

Gnomad EAS AF: 0.671

Gnomad SAS AF: 0.498

Gnomad FIN AF: 0.416

Gnomad MID AF: 0.449

Gnomad NFE AF: 0.390

Gnomad OTH AF: 0.470

GnomAD3 exomes AF: 0.468 AC: 117139 AN: 250304 Hom.: 28501 AF XY: 0.461 AC XY: 62310 AN XY: 135262

Gnomad AFR exome AF: 0.535

Gnomad AMR exome AF: 0.583

Gnomad ASJ exome AF: 0.464

Gnomad EAS exome AF: 0.677

Gnomad SAS exome AF: 0.493

Gnomad FIN exome AF: 0.402

Gnomad NFE exome AF: 0.396

Gnomad OTH exome AF: 0.458

GnomAD4 exome AF: 0.417 AC: 609141 AN: 1461030 Hom.: 130815 Cov.: 45 AF XY: 0.418 AC XY: 303811 AN XY: 726818

Gnomad4 AFR exome AF: 0.540

Gnomad4 AMR exome AF: 0.575

Gnomad4 ASJ exome AF: 0.464

Gnomad4 EAS exome AF: 0.674

Gnomad4 SAS exome AF: 0.492

Gnomad4 FIN exome AF: 0.398

Gnomad4 NFE exome AF: 0.390

Gnomad4 OTH exome AF: 0.443

GnomAD4 genome AF: 0.464 AC: 70518 AN: 152094 Hom.: 16804 Cov.: 33 AF XY: 0.468 AC XY: 34825 AN XY: 74340

Gnomad4 AFR AF: 0.542

Gnomad4 AMR AF: 0.520

Gnomad4 ASJ AF: 0.486

Gnomad4 EAS AF: 0.671

Gnomad4 SAS AF: 0.498

Gnomad4 FIN AF: 0.416

Gnomad4 NFE AF: 0.390

Gnomad4 OTH AF: 0.465

Alfa AF: 0.415 Hom.: 10283

Bravo AF: 0.477

TwinsUK AF: 0.382 AC: 1418

ALSPAC AF: 0.395 AC: 1522

ESP6500AA AF: 0.520 AC: 2293

ESP6500EA AF: 0.405 AC: 3486

ExAC AF: 0.465 AC: 56449

Asia WGS AF: 0.570 AC: 1982 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 17, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Vitelliform macular dystrophy 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 19, 2021

- -

Retinal dystrophy Benign:1

Benign, criteria provided, single submitter

research

Dept Of Ophthalmology, Nagoya University

Oct 01, 2023

- -

Benign concentric annular macular dystrophy Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 19, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.048
BayesDel_addAF	Benign	-0.83	T
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.5
DANN	Benign	0.43
DEOGEN2	Benign	0.000033	T;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.00025	N
LIST_S2	Benign	0.16	T;T
MetaRNN	Benign	0.0000027	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-2.3	N;.
PrimateAI	Benign	0.29	T
PROVEAN	Benign	1.8	N;.
REVEL	Benign	0.061
Sift	Benign	1.0	T;.
Sift4G	Benign	0.72	T;T
Polyphen		0.0	B;.
Vest4		0.025
MPC		0.013
ClinPred		0.0013	T
GERP RS		1.5
Varity_R		0.058
gMVP		0.14

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

Other links and lift over

dbSNP: rs3734311; hg19: chr6-76660551; COSMIC: COSV64058198;