12-66347705-C-T

Position:

• chr12-66347705-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Moderate BP6_Very_Strong BS2

The NM_001366722.1(GRIP1):​c.*1314G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0038 in 151,770 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0038 (5 hom., cov: 33)
  • Failed GnomAD Quality Control
• Consequence: GRIP1 NM_001366722.1 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.36

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant 12-66347705-C-T is Benign according to our data. Variant chr12-66347705-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 310272.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRIP1	NM_001366722.1	c.*1314G>A		3_prime_UTR_variant	25/25	ENST00000359742.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRIP1	ENST00000359742.9	c.*1314G>A		3_prime_UTR_variant	25/25	5	NM_001366722.1	P1
GRIP1	ENST00000398016.7	c.*1314G>A		3_prime_UTR_variant	24/24	1
GRIP1	ENST00000696989.1	c.*1314G>A		3_prime_UTR_variant	23/23

Frequencies

GnomAD3 genomes AF: 0.00380 AC: 577 AN: 151656 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.0122

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00462

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000624

Gnomad FIN AF: 0.0000952

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.000368

Gnomad OTH AF: 0.00385

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

GnomAD4 genome AF: 0.00380 AC: 576 AN: 151770 Hom.: 5 Cov.: 33 AF XY: 0.00344 AC XY: 255 AN XY: 74162

Gnomad4 AFR AF: 0.0122

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.00462

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000625

Gnomad4 FIN AF: 0.0000952

Gnomad4 NFE AF: 0.000368

Gnomad4 OTH AF: 0.00381

Alfa AF: 0.000751 Hom.: 0

Bravo AF: 0.00448

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Fraser syndrome 3 Benign:1

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	6.8
DANN	Benign	0.61

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: rs144894732; hg19: chr12-66741485; COSMIC: COSV54035649; COSMIC: COSV54035649;