chr12-66517991-G-T

Variant names:

• chr12-66517991-G-T
• rs11838180
• NM_001366722.1:c.503-15C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001379345.1(GRIP1):​c.581-15C>A variant causes a 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_001379345.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.118
• Publications: 10 publications found

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: G2P, ClinGen, Labcorp Genetics (formerly Invitae)
• Fraser syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 261412.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.306 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001379345.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRIP1	NM_001366722.1	MANE Select	c.503-15C>A		intron	N/A	NP_001353651.1
	GRIP1	NM_001379345.1		c.581-15C>A		intron	N/A	NP_001366274.1
	GRIP1	NM_001439322.1		c.506-15C>A		intron	N/A	NP_001426251.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRIP1	ENST00000359742.9	TSL:5 MANE Select	c.503-15C>A		intron	N/A	ENSP00000352780.4
	GRIP1	ENST00000398016.7	TSL:1	c.503-15C>A		intron	N/A	ENSP00000381098.3
	GRIP1	ENST00000536215.5	TSL:1	c.335-15C>A		intron	N/A	ENSP00000446011.1

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

GnomAD2 exomes AF: 0.240 AC: 59827 AN: 248892 AF XY: 0.247

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 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

African (AFR) AF: 0.309 AC: 9407 AN: 30452

American (AMR) AF: 0.147 AC: 6538 AN: 44500

Ashkenazi Jewish (ASJ) AF: 0.294 AC: 7395 AN: 25134

East Asian (EAS) AF: 0.130 AC: 5070 AN: 38952

South Asian (SAS) AF: 0.264 AC: 21972 AN: 83072

European-Finnish (FIN) AF: 0.202 AC: 10729 AN: 53080

Middle Eastern (MID) AF: 0.285 AC: 1558 AN: 5468

European-Non Finnish (NFE) AF: 0.267 AC: 258239 AN: 966892

Other (OTH) AF: 0.266 AC: 14662 AN: 55044

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

African (AFR) AF: 0.311 AC: 12871 AN: 41398

American (AMR) AF: 0.225 AC: 3427 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.292 AC: 1010 AN: 3464

East Asian (EAS) AF: 0.149 AC: 769 AN: 5160

South Asian (SAS) AF: 0.249 AC: 1193 AN: 4800

European-Finnish (FIN) AF: 0.203 AC: 2144 AN: 10556

Middle Eastern (MID) AF: 0.332 AC: 97 AN: 292

European-Non Finnish (NFE) AF: 0.272 AC: 18456 AN: 67918

Other (OTH) AF: 0.290 AC: 611 AN: 2108

Alfa AF: 0.271 Hom.: 18104

Bravo AF: 0.269

Asia WGS AF: 0.229 AC: 799 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Fraser syndrome 1 (2)
-	-	2	Fraser syndrome 3 (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	7.9
DANN	Benign	0.49
PhyloP100		0.12
PromoterAI		-0.022	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs11838180; hg19: chr12-66911771; COSMIC: COSV107266863; COSMIC: COSV107266863;