12-66463002-C-T

Variant names:

• chr12-66463002-C-T
• rs17102531
• NM_001366722.1:c.964G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001366722.1(GRIP1):​c.964G>A​(p.Ala322Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00242 in 1,613,768 control chromosomes in the GnomAD database, including 99 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (46 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (53 hom.)
• Consequence: GRIP1 NM_001366722.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 4.88
• Publications: 8 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0043607056).
• BP6: Variant 12-66463002-C-T is Benign according to our data. Variant chr12-66463002-C-T is described in ClinVar as Benign. ClinVar VariationId is 310310.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 = 0.0122 (1852/152068) while in subpopulation AFR AF = 0.0417 (1728/41462). AF 95% confidence interval is 0.04. There are 46 homozygotes in GnomAd4. There are 856 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 46 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.964G>A	p.Ala322Thr	missense	Exon 9 of 25	NP_001353651.1	Q9Y3R0-1
	GRIP1	NM_001379345.1		c.1042G>A	p.Ala348Thr	missense	Exon 9 of 25	NP_001366274.1
	GRIP1	NM_001439322.1		c.967G>A	p.Ala323Thr	missense	Exon 9 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.964G>A	p.Ala322Thr	missense	Exon 9 of 25	ENSP00000352780.4	Q9Y3R0-1
	GRIP1	ENST00000398016.7	TSL:1	c.964G>A	p.Ala322Thr	missense	Exon 9 of 24	ENSP00000381098.3	Q9Y3R0-3
	GRIP1	ENST00000536215.5	TSL:1	c.796G>A	p.Ala266Thr	missense	Exon 8 of 19	ENSP00000446011.1	F5H4Q7

Frequencies

GnomAD3 genomes AF: 0.0122 AC: 1853 AN: 151952 Hom.: 46 Cov.: 32

Gnomad AFR AF: 0.0418

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00465

Gnomad ASJ AF: 0.00404

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000945

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.0110

GnomAD2 exomes AF: 0.00343 AC: 855 AN: 249260 AF XY: 0.00274

Gnomad AFR exome AF: 0.0450

Gnomad AMR exome AF: 0.00232

Gnomad ASJ exome AF: 0.00378

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000256

Gnomad OTH exome AF: 0.00198

GnomAD4 exome AF: 0.00141 AC: 2057 AN: 1461700 Hom.: 53 Cov.: 32 AF XY: 0.00119 AC XY: 866 AN XY: 727146

African (AFR) AF: 0.0445 AC: 1489 AN: 33470

American (AMR) AF: 0.00284 AC: 127 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00398 AC: 104 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86226

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53404

Middle Eastern (MID) AF: 0.00208 AC: 12 AN: 5768

European-Non Finnish (NFE) AF: 0.0000980 AC: 109 AN: 1111904

Other (OTH) AF: 0.00351 AC: 212 AN: 60392

GnomAD4 genome AF: 0.0122 AC: 1852 AN: 152068 Hom.: 46 Cov.: 32 AF XY: 0.0115 AC XY: 856 AN XY: 74358

African (AFR) AF: 0.0417 AC: 1728 AN: 41462

American (AMR) AF: 0.00465 AC: 71 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00404 AC: 14 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5154

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.0000945 AC: 1 AN: 10586

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 67986

Other (OTH) AF: 0.0109 AC: 23 AN: 2108

Alfa AF: 0.00414 Hom.: 40

Bravo AF: 0.0144

ESP6500AA AF: 0.0393 AC: 159

ESP6500EA AF: 0.000476 AC: 4

ExAC AF: 0.00421 AC: 509

EpiCase AF: 0.000218

EpiControl AF: 0.000296

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.36
CADD	Pathogenic	26
DANN	Benign	0.97
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.070
Eigen_PC	Benign	-0.052
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.97	D
MetaRNN	Benign	0.0044	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	2.0	M
PhyloP100		4.9
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-2.5	D
REVEL	Benign	0.23
Sift	Benign	0.040	D
Sift4G	Benign	0.17	T
Polyphen		0.35	B
Vest4		0.45
MVP		0.35
MPC		0.79
ClinPred		0.047	T
GERP RS		4.2
Varity_R		0.55
gMVP		0.29
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs17102531; hg19: chr12-66856782; COSMIC: COSV99064738;