chr12-66348261-GATAAT-G

Variant names:

• chr12-66348261-GATAAT-G
• rs886049793
• NM_001366722.1:c.*753_*757delATTAT

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BS1_Supporting

The NM_001366722.1(GRIP1):​c.*753_*757delATTAT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000442 in 151,700 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00044 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GRIP1 NM_001366722.1 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.424
• 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: Likely_benign. The variant received -1 ACMG points.

• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000442 (67/151700) while in subpopulation NFE AF = 0.000206 (14/67950). AF 95% confidence interval is 0.000124. There are 0 homozygotes in GnomAd4. There are 27 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.*753_*757delATTAT		3_prime_UTR	Exon 25 of 25	NP_001353651.1	Q9Y3R0-1
	GRIP1	NM_001379345.1		c.*753_*757delATTAT		3_prime_UTR	Exon 25 of 25	NP_001366274.1
	GRIP1	NM_001439322.1		c.*753_*757delATTAT		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.*753_*757delATTAT		3_prime_UTR	Exon 25 of 25	ENSP00000352780.4	Q9Y3R0-1
	GRIP1	ENST00000398016.7	TSL:1	c.*753_*757delATTAT		3_prime_UTR	Exon 24 of 24	ENSP00000381098.3	Q9Y3R0-3
	GRIP1	ENST00000696989.1		c.*753_*757delATTAT		3_prime_UTR	Exon 23 of 23	ENSP00000513025.1	A0A8V8TLS6

Frequencies

GnomAD3 genomes AF: 0.000442 AC: 67 AN: 151700 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000194

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.0118

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.000960

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 4 Hom.: 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) AF: 0.00 AC: 0 AN: 4

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.000442 AC: 67 AN: 151700 Hom.: 0 Cov.: 32 AF XY: 0.000365 AC XY: 27 AN XY: 74054

African (AFR) AF: 0.000194 AC: 8 AN: 41240

American (AMR) AF: 0.000131 AC: 2 AN: 15218

Ashkenazi Jewish (ASJ) AF: 0.0118 AC: 41 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10506

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 67950

Other (OTH) AF: 0.000960 AC: 2 AN: 2084

Alfa AF: 0.000712 Hom.: 0

Bravo AF: 0.000559

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Fraser syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.42

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs886049793; hg19: chr12-66742041;