rs199768740

Positions:

chr12-66541927-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_001366722.1(GRIP1):c.160G>A(p.Val54Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000954 in 1,613,946 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). Synonymous variant affecting the same amino acid position (i.e. V54V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00091 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00096 ( 5 hom. )

Consequence

GRIP1
NM_001366722.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:5B:2

Conservation

PhyloP100: 7.91

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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010997534).

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000959 (1402/1461706) while in subpopulation MID AF= 0.0168 (97/5768). AF 95% confidence interval is 0.0141. There are 5 homozygotes in gnomad4_exome. There are 727 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRIP1	NM_001366722.1 linkuse as main transcript	c.160G>A	p.Val54Ile	missense_variant	3/25	ENST00000359742.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRIP1	ENST00000359742.9 linkuse as main transcript	c.160G>A	p.Val54Ile	missense_variant	3/25	5	NM_001366722.1	P1	Q9Y3R0-1

Frequencies

GnomAD3 genomes

AF:

0.000907

AC:

138

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00164

Gnomad ASJ

AF:

0.00720

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000830

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.000941

Gnomad OTH

AF:

0.00335

GnomAD3 exomes

AF:

0.00126

AC:

313

AN:

249328

Hom.:

AF XY:

0.00123

AC XY:

166

AN XY:

135246

show subpopulations

Gnomad AFR exome

AF:

0.000194

Gnomad AMR exome

AF:

0.00148

Gnomad ASJ exome

AF:

0.00586

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00134

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00128

Gnomad OTH exome

AF:

0.00231

GnomAD4 exome

AF:

0.000959

AC:

1402

AN:

1461706

Hom.:

Cov.:

AF XY:

0.00100

AC XY:

727

AN XY:

727164

show subpopulations

Gnomad4 AFR exome

AF:

0.000269

Gnomad4 AMR exome

AF:

0.00174

Gnomad4 ASJ exome

AF:

0.00632

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00145

Gnomad4 FIN exome

AF:

0.0000374

Gnomad4 NFE exome

AF:

0.000727

Gnomad4 OTH exome

AF:

0.00195

GnomAD4 genome

AF:

0.000906

AC:

138

AN:

152240

Hom.:

Cov.:

AF XY:

0.000873

AC XY:

AN XY:

74432

show subpopulations

Gnomad4 AFR

AF:

0.000217

Gnomad4 AMR

AF:

0.00163

Gnomad4 ASJ

AF:

0.00720

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000831

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000941

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.00128

Hom.:

Bravo

AF:

0.00112

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000263

AC:

ESP6500EA

AF:

0.000972

AC:

ExAC

AF:

0.00123

AC:

149

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00185

EpiControl

AF:

0.00213

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:5Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Fraser syndrome 3

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Daryl Scott Lab, Baylor College of Medicine	Feb 01, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 08, 2018	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. -
Likely benign, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -

Abnormal brain morphology

Pathogenic:1Uncertain:1

Likely pathogenic, flagged submission	research	Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	-	- -
Uncertain significance, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	NM_021150.3:c.160G>A in the GRIP1 gene has an allele frequency of 0.006 in Ashkenazi Jewish subpopulation in the gnomAD database. Karaca et al. identified c.160G>A compound with c.1142G>T (phase unknown) in a neurologic patient. Two variants are novel with high frequency in Turkish Exomes (PMID: 26539891). We interpret it as a variant of uncertain significance. ACMG/AMP criteria applied: Null. -

not provided

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	New York Genome Center	Dec 13, 2019	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Apr 14, 2022

Variant summary: GRIP1 c.160G>A (p.Val54Ile) 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 damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0013 in 249328 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in GRIP1 causing Cryptophthalmos Syndrome (0.0013 vs 0.0013), allowing no conclusion about variant significance. c.160G>A has been reported in the literature in one compound heterozygous individual affected with agenesis of the corpus callosum and subependymal heterotopia (Karaca_2015). These data do not allow any conclusion about variant significance with Cryptophthalmos Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters have assessed the variant since 2014: three classify the variant as of uncertain significance, one as likely benign, and one as likely pathogenic. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.29

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.28

.;T;T;.;T

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.91

D;D;D;D;D

M_CAP

Benign

0.018

MetaRNN

Benign

0.011

T;T;T;T;T

MetaSVM

Benign

-0.71

MutationAssessor

Benign

1.8

L;L;.;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-0.69

N;N;N;N;N

REVEL

Benign

0.24

Sift

Uncertain

0.0060

D;D;D;T;D

Sift4G

Uncertain

0.015

D;D;.;.;.

Polyphen

1.0

D;.;D;.;.

Vest4

0.62

MVP

0.43

MPC

0.42

ClinPred

0.83

GERP RS

5.4

Varity_R

0.24

gMVP

0.31

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

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