rs11838180

Positions:

• chr12-66517991-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001366722.1(GRIP1):​c.503-15C>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.259 in 1,454,456 control chromosomes in the GnomAD database, including 50,228 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (5667 hom., cov: 32)
  • Exomes 𝑓: 0.26 (44561 hom.)
• Consequence: GRIP1 NM_001366722.1 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.118

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 12-66517991-G-T is Benign according to our data. Variant chr12-66517991-G-T is described in ClinVar as [Benign]. Clinvar id is 261412.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-66517991-G-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.306 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRIP1	NM_001366722.1	c.503-15C>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000359742.9	NP_001353651.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GRIP1	ENST00000359742.9	c.503-15C>A		splice_polypyrimidine_tract_variant, intron_variant		5	NM_001366722.1	ENSP00000352780	P1

Frequencies

GnomAD3 genomes AF: 0.269 AC: 40835 AN: 151744 Hom.: 5662 Cov.: 32

Gnomad AFR AF: 0.311

Gnomad AMI AF: 0.316

Gnomad AMR AF: 0.225

Gnomad ASJ AF: 0.292

Gnomad EAS AF: 0.149

Gnomad SAS AF: 0.248

Gnomad FIN AF: 0.203

Gnomad MID AF: 0.350

Gnomad NFE AF: 0.272

Gnomad OTH AF: 0.284

GnomAD3 exomes AF: 0.240 AC: 59827 AN: 248892 Hom.: 7761 AF XY: 0.247 AC XY: 33300 AN XY: 135036

Gnomad AFR exome AF: 0.314

Gnomad AMR exome AF: 0.138

Gnomad ASJ exome AF: 0.296

Gnomad EAS exome AF: 0.157

Gnomad SAS exome AF: 0.264

Gnomad FIN exome AF: 0.199

Gnomad NFE exome AF: 0.270

Gnomad OTH exome AF: 0.273

GnomAD4 exome AF: 0.258 AC: 335570 AN: 1302594 Hom.: 44561 Cov.: 21 AF XY: 0.259 AC XY: 170298 AN XY: 656872

Gnomad4 AFR exome AF: 0.309

Gnomad4 AMR exome AF: 0.147

Gnomad4 ASJ exome AF: 0.294

Gnomad4 EAS exome AF: 0.130

Gnomad4 SAS exome AF: 0.264

Gnomad4 FIN exome AF: 0.202

Gnomad4 NFE exome AF: 0.267

Gnomad4 OTH exome AF: 0.266

GnomAD4 genome AF: 0.269 AC: 40866 AN: 151862 Hom.: 5667 Cov.: 32 AF XY: 0.266 AC XY: 19753 AN XY: 74212

Gnomad4 AFR AF: 0.311

Gnomad4 AMR AF: 0.225

Gnomad4 ASJ AF: 0.292

Gnomad4 EAS AF: 0.149

Gnomad4 SAS AF: 0.249

Gnomad4 FIN AF: 0.203

Gnomad4 NFE AF: 0.272

Gnomad4 OTH AF: 0.290

Alfa AF: 0.272 Hom.: 11905

Bravo AF: 0.269

Asia WGS AF: 0.229 AC: 799 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 15, 2018	- -

Fraser syndrome 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Fraser syndrome 3 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	7.9
DANN	Benign	0.49

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

Other links and lift over

dbSNP: rs11838180; hg19: chr12-66911771;