Genetic Variant GRIP1:p.Ile586Leu (chr12-66432560-T-G) – ACMG Classification: Benign (-13 pts)

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: Labcorp Genetics (formerly Invitae), G2P, ClinGen
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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001366722.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GRIP1	NM_001366722.1	MANE Select	c.1756A>C	p.Ile586Leu	missense	Exon 14 of 25	NP_001353651.1	Q9Y3R0-1
GRIP1	NM_001379345.1		c.1834A>C	p.Ile612Leu	missense	Exon 14 of 25	NP_001366274.1
GRIP1	NM_001439322.1		c.1759A>C	p.Ile587Leu	missense	Exon 14 of 24	NP_001426251.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GRIP1	ENST00000359742.9	TSL:5 MANE Select	c.1756A>C	p.Ile586Leu	missense	Exon 14 of 25	ENSP00000352780.4	Q9Y3R0-1
GRIP1	ENST00000398016.7	TSL:1	c.1600A>C	p.Ile534Leu	missense	Exon 13 of 24	ENSP00000381098.3	Q9Y3R0-3
GRIP1	ENST00000536215.5	TSL:1	c.1276A>C	p.Ile426Leu	missense	Exon 11 of 19	ENSP00000446011.1	F5H4Q7

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

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (6)

Fraser syndrome 3 (2)

not specified (2)

GRIP1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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

0.19

Eigen

Benign

0.099

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.95

M_CAP

Benign

0.012

MetaRNN

Benign

0.014

MetaSVM

Benign

-0.89

MutationAssessor

Benign

1.5

PhyloP100

6.3

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

-1.6

REVEL

Benign

0.18

Sift

Benign

0.084

Sift4G

Benign

0.14

Polyphen

0.032

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

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over