chr12-66392391-A-C

Position:

chr12-66392391-A-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001366722.1(GRIP1):c.2381T>G(p.Met794Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00153 in 1,613,954 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0016 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0015 ( 13 hom. )

Consequence

GRIP1
NM_001366722.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:8

Conservation

PhyloP100: 1.61

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008709252).

BP6

Variant 12-66392391-A-C is Benign according to our data. Variant chr12-66392391-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 227419.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=1}. Variant chr12-66392391-A-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00153 (2238/1461688) while in subpopulation MID AF= 0.0196 (113/5768). AF 95% confidence interval is 0.0167. There are 13 homozygotes in gnomad4_exome. There are 1156 alleles in male gnomad4_exome subpopulation. Median coverage is 34. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRIP1	NM_001366722.1 linkuse as main transcript	c.2381T>G	p.Met794Arg	missense_variant	19/25	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.2381T>G	p.Met794Arg	missense_variant	19/25	5	NM_001366722.1	ENSP00000352780	P1	Q9Y3R0-1

Frequencies

GnomAD3 genomes

AF:

0.00156

AC:

237

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000338

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00157

Gnomad ASJ

AF:

0.000864

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000828

Gnomad FIN

AF:

0.00141

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.00240

Gnomad OTH

AF:

0.00335

GnomAD3 exomes

AF:

0.00164

AC:

410

AN:

249376

Hom.:

AF XY:

0.00175

AC XY:

237

AN XY:

135278

show subpopulations

Gnomad AFR exome

AF:

0.0000646

Gnomad AMR exome

AF:

0.00142

Gnomad ASJ exome

AF:

0.00109

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000784

Gnomad FIN exome

AF:

0.00111

Gnomad NFE exome

AF:

0.00252

Gnomad OTH exome

AF:

0.00264

GnomAD4 exome

AF:

0.00153

AC:

2238

AN:

1461688

Hom.:

Cov.:

AF XY:

0.00159

AC XY:

1156

AN XY:

727174

show subpopulations

Gnomad4 AFR exome

AF:

0.000418

Gnomad4 AMR exome

AF:

0.00181

Gnomad4 ASJ exome

AF:

0.000727

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000951

Gnomad4 FIN exome

AF:

0.00230

Gnomad4 NFE exome

AF:

0.00152

Gnomad4 OTH exome

AF:

0.00184

GnomAD4 genome

AF:

0.00156

AC:

237

AN:

152266

Hom.:

Cov.:

AF XY:

0.00152

AC XY:

113

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.000337

Gnomad4 AMR

AF:

0.00157

Gnomad4 ASJ

AF:

0.000864

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000829

Gnomad4 FIN

AF:

0.00141

Gnomad4 NFE

AF:

0.00240

Gnomad4 OTH

AF:

0.00332

Alfa

AF:

0.00236

Hom.:

Bravo

AF:

0.00139

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000246

AC:

ESP6500EA

AF:

0.00143

AC:

ExAC

AF:

0.00178

AC:

216

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00322

EpiControl

AF:

0.00273

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:4

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 26, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	GRIP1: BP4, BS2 -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 15, 2015	p.Met742Arg in exon 18 of GRIP1: This variant is not expected to have clinical s ignificance because it has been identified in 0.3% (172/66736) of European chrom osomes (including one homozygote individual) by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs144494437). It has been reported in 1 individual with autism and segregated with disease in 1 affected relative (Mejias 2011), however the proband was homozygous for the variant and the relati ve was heterozygous for the variant. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 28, 2022	Variant summary: GRIP1 c.2225T>G (p.Met742Arg) results in a non-conservative amino acid change located in the PDZ domain (IPR001478) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0017 in 280778 control chromosomes (gnomAD), with 2 homozygotes. The variant occurs predominantly at a frequency of 0.0027 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 (0.0013), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no occurrence of c.2225T>G in individuals affected with Cryptophthalmos Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Six ClinVar submitters have assessed the variant since 2014: one classified the variant as VUS, and five as likely benign. Based on the evidence outlined above, the variant was classified as likely benign. -

Intellectual disability

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Jan 01, 2019

- -

Fraser syndrome 3

Benign:1

Likely benign, 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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.19

CADD

Benign

DANN

Benign

0.38

DEOGEN2

Benign

0.22

.;T;T;T;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.27

LIST_S2

Benign

0.75

T;T;T;T;T

M_CAP

Benign

0.041

MetaRNN

Benign

0.0087

T;T;T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

-0.050

.;N;.;.;.

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.26

PROVEAN

Benign

-1.1

N;N;N;N;N

REVEL

Uncertain

0.47

Sift

Benign

0.38

T;T;T;T;T

Sift4G

Benign

0.51

T;T;.;T;.

Polyphen

0.0

B;B;B;.;.

Vest4

0.21

MVP

0.95

MPC

0.44

ClinPred

0.0041

GERP RS

-2.1

Varity_R

0.15

gMVP

0.34

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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