Genetic Variant GRIP1:p.Ser433Ile (chr12-66455465-C-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP5_Moderate

The NM_001366722.1(GRIP1):c.1298G>T(p.Ser433Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Consequence

GRIP1
NM_001366722.1 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 7.91

Publications

3 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 12-66455465-C-A is Pathogenic according to our data. Variant chr12-66455465-C-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 402209.Status of the report is criteria_provided_single_submitter, 1 stars.

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.1298G>T	p.Ser433Ile	missense	Exon 11 of 25	NP_001353651.1	Q9Y3R0-1
GRIP1	NM_001379345.1		c.1376G>T	p.Ser459Ile	missense	Exon 11 of 25	NP_001366274.1
GRIP1	NM_001439322.1		c.1301G>T	p.Ser434Ile	missense	Exon 11 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.1298G>T	p.Ser433Ile	missense	Exon 11 of 25	ENSP00000352780.4	Q9Y3R0-1
GRIP1	ENST00000398016.7	TSL:1	c.1142G>T	p.Ser381Ile	missense	Exon 10 of 24	ENSP00000381098.3	Q9Y3R0-3
GRIP1	ENST00000536215.5	TSL:1	c.874+7459G>T		intron	N/A	ENSP00000446011.1	F5H4Q7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Likely pathogenic

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Abnormal brain morphology (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.87

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Uncertain

0.10

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.69

Eigen

Pathogenic

0.80

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

M_CAP

Benign

0.074

MetaRNN

Uncertain

0.63

MetaSVM

Benign

-0.89

MutationAssessor

Uncertain

2.6

PhyloP100

7.9

PrimateAI

Uncertain

0.76

PROVEAN

Uncertain

-3.3

REVEL

Uncertain

0.41

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0040

Polyphen

1.0

Vest4

0.73

MutPred

0.38

Loss of phosphorylation at S381 (P = 0.0091)

MVP

0.43

MPC

1.1

ClinPred

0.98

GERP RS

5.5

Varity_R

0.54

gMVP

0.77

Mutation Taster

=3/97

disease causing (ClinVar)

(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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over