chr12-66347705-C-T

Variant names:

• chr12-66347705-C-T
• rs144894732
• NM_001366722.1:c.*1314G>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 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
• Publications: 0 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: Labcorp Genetics (formerly Invitae), G2P, ClinGen
• Fraser syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -18 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 VariationId is 310272.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0038 (576/151770) while in subpopulation AFR AF = 0.0122 (504/41298). AF 95% confidence interval is 0.0113. There are 5 homozygotes in GnomAd4. There are 255 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRIP1	NM_001366722.1	MANE Select	c.*1314G>A		3_prime_UTR	Exon 25 of 25	NP_001353651.1	Q9Y3R0-1
	GRIP1	NM_001379345.1		c.*1314G>A		3_prime_UTR	Exon 25 of 25	NP_001366274.1
	GRIP1	NM_001439322.1		c.*1314G>A		3_prime_UTR	Exon 24 of 24	NP_001426251.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRIP1	ENST00000359742.9	TSL:5 MANE Select	c.*1314G>A		3_prime_UTR	Exon 25 of 25	ENSP00000352780.4	Q9Y3R0-1
	GRIP1	ENST00000398016.7	TSL:1	c.*1314G>A		3_prime_UTR	Exon 24 of 24	ENSP00000381098.3	Q9Y3R0-3
	GRIP1	ENST00000696989.1		c.*1314G>A		3_prime_UTR	Exon 23 of 23	ENSP00000513025.1	A0A8V8TLS6

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

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AC: 0 AN: 0

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

African (AFR) AF: 0.0122 AC: 504 AN: 41298

American (AMR) AF: 0.00118 AC: 18 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00462 AC: 16 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000625 AC: 3 AN: 4800

European-Finnish (FIN) AF: 0.0000952 AC: 1 AN: 10502

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.000368 AC: 25 AN: 67950

Other (OTH) AF: 0.00381 AC: 8 AN: 2100

Alfa AF: 0.00136 Hom.: 0

Bravo AF: 0.00448

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	6.8
DANN	Benign	0.61
PhyloP100		1.4
Mutation Taster		=100/0	polymorphism

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