dbSNP rs144494437: GRIP1:p.Met794Arg (chr12-66392391-A-C) – 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.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. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M794T) has been classified as Uncertain significance.

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

Publications

7 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=0.008709252).

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 VariationId is 227419.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00156 (237/152266) while in subpopulation NFE AF = 0.0024 (163/68020). AF 95% confidence interval is 0.0021. There are 1 homozygotes in GnomAd4. There are 113 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 13 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.2381T>G	p.Met794Arg	missense	Exon 19 of 25	NP_001353651.1	Q9Y3R0-1
GRIP1	NM_001379345.1		c.2459T>G	p.Met820Arg	missense	Exon 19 of 25	NP_001366274.1
GRIP1	NM_001439322.1		c.2384T>G	p.Met795Arg	missense	Exon 19 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.2381T>G	p.Met794Arg	missense	Exon 19 of 25	ENSP00000352780.4	Q9Y3R0-1
GRIP1	ENST00000398016.7	TSL:1	c.2225T>G	p.Met742Arg	missense	Exon 18 of 24	ENSP00000381098.3	Q9Y3R0-3
GRIP1	ENST00000536215.5	TSL:1	c.1901T>G	p.Met634Arg	missense	Exon 16 of 19	ENSP00000446011.1	F5H4Q7

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

GnomAD2 exomes

AF:

0.00164

AC:

410

AN:

249376

AF XY:

0.00175

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 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

African (AFR)

AF:

0.000418

AC:

AN:

33480

American (AMR)

AF:

0.00181

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000727

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000951

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00230

AC:

123

AN:

53420

Middle Eastern (MID)

AF:

0.0196

AC:

113

AN:

5768

European-Non Finnish (NFE)

AF:

0.00152

AC:

1695

AN:

1111814

Other (OTH)

AF:

0.00184

AC:

111

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

119

237

356

474

593

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

144

192

240

<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:

0.00156

AC:

237

AN:

152266

Hom.:

Cov.:

AF XY:

0.00152

AC XY:

113

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.000337

AC:

AN:

41562

American (AMR)

AF:

0.00157

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.000864

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5162

South Asian (SAS)

AF:

0.000829

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00141

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00240

AC:

163

AN:

68020

Other (OTH)

AF:

0.00332

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00222

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

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

not specified (2)

Fraser syndrome 3 (1)

Intellectual disability (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.19

CADD

Benign

(source)

DANN

Benign

0.38

DEOGEN2

Benign

0.22

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.27

LIST_S2

Benign

0.75

M_CAP

Benign

0.041

MetaRNN

Benign

0.0087

MetaSVM

Benign

-0.98

MutationAssessor

Benign

-0.050

PhyloP100

1.6

PrimateAI

Benign

0.26

PROVEAN

Benign

-1.1

REVEL

Uncertain

0.47

Sift

Benign

0.38

Sift4G

Benign

0.51

Polyphen

0.0

Vest4

0.21

MVP

0.95

MPC

0.44

ClinPred

0.0041

GERP RS

-2.1

Varity_R

0.15

gMVP

0.34

Mutation Taster

=98/2

polymorphism

(source)

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

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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