12-66432560-T-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

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

Publications

4 publications found

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 Gene-Disease associations (from GenCC):

Fraser syndrome 3
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae)
Fraser syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

GRIP1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 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 VariationId is 265191.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00146 (222/152328) while in subpopulation NFE AF = 0.0024 (163/68018). AF 95% confidence interval is 0.0021. There are 0 homozygotes in GnomAd4. There are 98 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRIP1	NM_001366722.1 link	c.1756A>C	p.Ile586Leu	missense_variant	Exon 14 of 25	ENST00000359742.9	NP_001353651.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRIP1	ENST00000359742.9 link	c.1756A>C	p.Ile586Leu	missense_variant	Exon 14 of 25	5	NM_001366722.1	ENSP00000352780.4

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

GnomAD2 exomes

AF:

0.00128

AC:

318

AN:

248122

AF XY:

0.00134

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 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

African (AFR)

AF:

0.000456

AC:

AN:

32922

American (AMR)

AF:

0.00110

AC:

AN:

44596

Ashkenazi Jewish (ASJ)

AF:

0.0000771

AC:

AN:

25952

East Asian (EAS)

AF:

0.00

AC:

AN:

39514

South Asian (SAS)

AF:

0.000549

AC:

AN:

85596

European-Finnish (FIN)

AF:

0.0000382

AC:

AN:

52328

Middle Eastern (MID)

AF:

0.000351

AC:

AN:

5706

European-Non Finnish (NFE)

AF:

0.00279

AC:

3025

AN:

1086078

Other (OTH)

AF:

0.00170

AC:

101

AN:

59366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

131

261

392

522

653

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

122

244

366

488

610

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00146

AC:

222

AN:

152328

Hom.:

Cov.:

AF XY:

0.00132

AC XY:

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.000649

AC:

AN:

41586

American (AMR)

AF:

0.00131

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00104

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00240

AC:

163

AN:

68018

Other (OTH)

AF:

0.00331

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00208

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

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Jan 04, 2018

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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.

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Jun 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

GRIP1: BS2

Fraser syndrome 3

Uncertain:2

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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.

Jan 29, 2018

Geisinger Autism and Developmental Medicine Institute, Geisinger Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing;provider interpretation

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.

not specified

Benign:2

Aug 13, 2018

Eurofins Ntd Llc (ga)

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Mar 07, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Aug 16, 2021

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0

.;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

0.0

.;L;.;.;.

PhyloP100

6.3

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;.

Vest4

0.62

ClinPred

0.023

GERP RS

5.8

Varity_R

0.35

gMVP

0.62

Mutation Taster

=98/2

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over