rs189438534

Positions:

chr12-66432560-T-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_001366722.1(GRIP1):c.1756A>C(p.Ile586Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00219 in 1,584,386 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0015 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0023 ( 5 hom. )

Consequence

GRIP1
NM_001366722.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:8

Conservation

PhyloP100: 6.30

Variant links:

Genes affected

GRIP1 (HGNC:18708): (glutamate receptor interacting protein 1) This gene encodes a member of the glutamate receptor interacting protein family. The encoded scaffold protein binds to and mediates the trafficking and membrane organization of a number of transmembrane proteins. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, May 2010]

GRIP1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.013707876).

BP6

Variant 12-66432560-T-G is Benign according to our data. Variant chr12-66432560-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 265191.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=3}. Variant chr12-66432560-T-G is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRIP1	NM_001366722.1 linkuse as main transcript	c.1756A>C	p.Ile586Leu	missense_variant	14/25	ENST00000359742.9	NP_001353651.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GRIP1	ENST00000359742.9 linkuse as main transcript	c.1756A>C	p.Ile586Leu	missense_variant	14/25	5	NM_001366722.1	ENSP00000352780.4		Q9Y3R0-1

Frequencies

GnomAD3 genomes

AF:

0.00146

AC:

222

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000651

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00240

Gnomad OTH

AF:

0.00334

GnomAD3 exomes

AF:

0.00128

AC:

318

AN:

248122

Hom.:

AF XY:

0.00134

AC XY:

180

AN XY:

134746

show subpopulations

Gnomad AFR exome

AF:

0.000389

Gnomad AMR exome

AF:

0.00122

Gnomad ASJ exome

AF:

0.000199

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000393

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00220

Gnomad OTH exome

AF:

0.00133

GnomAD4 exome

AF:

0.00226

AC:

3243

AN:

1432058

Hom.:

Cov.:

AF XY:

0.00218

AC XY:

1555

AN XY:

714236

show subpopulations

Gnomad4 AFR exome

AF:

0.000456

Gnomad4 AMR exome

AF:

0.00110

Gnomad4 ASJ exome

AF:

0.0000771

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000549

Gnomad4 FIN exome

AF:

0.0000382

Gnomad4 NFE exome

AF:

0.00279

Gnomad4 OTH exome

AF:

0.00170

GnomAD4 genome

AF:

0.00146

AC:

222

AN:

152328

Hom.:

Cov.:

AF XY:

0.00132

AC XY:

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.000649

Gnomad4 AMR

AF:

0.00131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00240

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.00223

Hom.:

Bravo

AF:

0.00155

TwinsUK

AF:

0.00216

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00159

AC:

ExAC

AF:

0.00119

AC:

144

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00262

EpiControl

AF:

0.00231

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:5

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2022	GRIP1: BS2 -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 04, 2018	The I534L variant in the GRIP1 gene was reported previously using alternate nomenclature I586L in an individual with autism and was absent in 480 control individuals (Mejias et al., 2011). Although not present in the homozygous state, the NHLBI ESP Exome Sequencing Project reports I534L was observed in 13/8166 alleles from individuals of European American background, indicating it may be a rare variant in this population. The I534L variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species. The I534L variant caused increased interaction, faster recycling, and increased surface distribution of glutamate receptor in live, transfected hippocampal neurons, suggesting gain-of-function (Mejias et al., 2011). We interpret I534L as a variant of uncertain significance. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Fraser syndrome 3

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing;provider interpretation	Geisinger Autism and Developmental Medicine Institute, Geisinger Health System	Jan 29, 2018	This is a 12 year old male with intellectual disability, autism spectrum disorder, mild hyptonia, hyperkinesis, and sleep problems. He has no history of seizures. This p.Ile534Leu variant is present in gnomAD non-Finnish European population at 0.22%. Computational prediction models are inconsistent. This patient does not have congenital anomalies that would be consistent with Fraser syndrome. This variant has been reported as a possible modifier of autism (Mejias, 2011) using alternate nomenclature (I586L). Whole exome sequencing identified a likely pathogenic, de novo variant in SCN2A and 1 additional variant of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 13, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 07, 2022	Variant summary: GRIP1 c.1600A>C (p.Ile534Leu) results in a conservative amino acid change located in the PDZ domain (IPR001478) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0013 in 248122 control chromosomes, predominantly at a frequency of 0.0022 within the Non-Finnish European subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2-fold of the estimated maximal expected allele frequency for a pathogenic variant in GRIP1 causing Cryptophthalmos Syndrome phenotype (0.0013), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.1600A>C has been reported in the literature in two heterozygous brothers affected with autism; it had been inherited from their unaffected mother (Mejias_2010). Experimental evidence provided by the authors demonstrated the variant was associated with altered interactions with glutamate receptors 2/3 in a yeast two-hybrid assay and faster recycling and increased surface distribution of GluA2 in rat neurons. This report does not provide unequivocal conclusions about association of the variant with Cryptophthalmos Syndrome. One ClinVar submitter (evaluation after 2014) cites the variant as likely benign and three ClinVar submitters (evaluation after 2014) cite it as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign for Cryptophthalmos Syndrome. -

GRIP1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 16, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.35

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Uncertain

-0.030

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.19

.;T;T;T;.

Eigen

Benign

0.099

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.95

D;D;D;D;D

M_CAP

Benign

0.012

MetaRNN

Benign

0.014

T;T;T;T;T

MetaSVM

Benign

-0.89

MutationAssessor

Benign

1.5

.;L;.;.;.

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

-1.6

N;N;N;N;N

REVEL

Benign

0.18

Sift

Benign

0.084

T;T;T;T;T

Sift4G

Benign

0.14

T;T;.;T;.

Polyphen

0.032

B;B;B;.;.

Vest4

0.62

MutPred

0.47

.;Gain of catalytic residue at S590 (P = 0);.;.;.;

MVP

0.58

MPC

0.80

ClinPred

0.023

GERP RS

5.8

Varity_R

0.35

gMVP

0.62

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

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