NM_020366.4:c.1797G>A

Variant names:

• chr14-21324652-G-A
• rs9322965
• NM_020366.4:c.1797G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_020366.4(RPGRIP1):​c.1797G>A​(p.Pro599Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.229 in 1,613,316 control chromosomes in the GnomAD database, including 44,140 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (3898 hom., cov: 32)
  • Exomes 𝑓: 0.23 (40242 hom.)
• Consequence: RPGRIP1 NM_020366.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8 O:1
• Conservation: PhyloP100: -0.372
• Publications: 16 publications found

Genes affected

RPGRIP1 (HGNC:13436): (RPGR interacting protein 1) This gene encodes a photoreceptor protein that interacts with retinitis pigmentosa GTPase regulator protein and is a key component of cone and rod photoreceptor cells. Mutations in this gene lead to autosomal recessive congenital blindness. [provided by RefSeq, Oct 2008]

RPGRIP1 Gene-Disease associations (from GenCC):

• cone-rod dystrophy 13

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, G2P
• Leber congenital amaurosis 6

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• cone-rod dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Leber congenital amaurosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.139).
• BP6: Variant 14-21324652-G-A is Benign according to our data. Variant chr14-21324652-G-A is described in ClinVar as Benign. ClinVar VariationId is 99812.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.372 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.254 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020366.4. 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
	RPGRIP1	NM_020366.4	MANE Select	c.1797G>A	p.Pro599Pro	synonymous	Exon 15 of 25	NP_065099.3
	RPGRIP1	NM_001377948.1		c.723G>A	p.Pro241Pro	synonymous	Exon 5 of 15	NP_001364877.1
	RPGRIP1	NM_001377949.1		c.723G>A	p.Pro241Pro	synonymous	Exon 5 of 13	NP_001364878.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPGRIP1	ENST00000400017.7	TSL:1 MANE Select	c.1797G>A	p.Pro599Pro	synonymous	Exon 15 of 25	ENSP00000382895.2	Q96KN7-1
	RPGRIP1	ENST00000555587.5	TSL:1	c.222G>A	p.Pro74Pro	synonymous	Exon 3 of 13	ENSP00000451262.1	G3V3I7
	RPGRIP1	ENST00000554303.1	TSL:1	c.183G>A	p.Pro61Pro	synonymous	Exon 3 of 3	ENSP00000450426.1	H0YIY1

Frequencies

GnomAD3 genomes AF: 0.220 AC: 33490 AN: 152024 Hom.: 3899 Cov.: 32

Gnomad AFR AF: 0.228

Gnomad AMI AF: 0.231

Gnomad AMR AF: 0.146

Gnomad ASJ AF: 0.184

Gnomad EAS AF: 0.0187

Gnomad SAS AF: 0.265

Gnomad FIN AF: 0.256

Gnomad MID AF: 0.271

Gnomad NFE AF: 0.241

Gnomad OTH AF: 0.205

GnomAD2 exomes AF: 0.207 AC: 51517 AN: 249100 AF XY: 0.214

Gnomad AFR exome AF: 0.226

Gnomad AMR exome AF: 0.105

Gnomad ASJ exome AF: 0.185

Gnomad EAS exome AF: 0.0159

Gnomad FIN exome AF: 0.259

Gnomad NFE exome AF: 0.239

Gnomad OTH exome AF: 0.217

GnomAD4 exome AF: 0.230 AC: 335615 AN: 1461174 Hom.: 40242 Cov.: 34 AF XY: 0.231 AC XY: 167974 AN XY: 726906

African (AFR) AF: 0.225 AC: 7545 AN: 33470

American (AMR) AF: 0.113 AC: 5056 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.179 AC: 4674 AN: 26132

East Asian (EAS) AF: 0.0195 AC: 775 AN: 39700

South Asian (SAS) AF: 0.273 AC: 23511 AN: 86246

European-Finnish (FIN) AF: 0.262 AC: 13939 AN: 53270

Middle Eastern (MID) AF: 0.237 AC: 1365 AN: 5768

European-Non Finnish (NFE) AF: 0.239 AC: 265119 AN: 1111506

Other (OTH) AF: 0.226 AC: 13631 AN: 60360

GnomAD4 genome AF: 0.220 AC: 33522 AN: 152142 Hom.: 3898 Cov.: 32 AF XY: 0.219 AC XY: 16282 AN XY: 74386

African (AFR) AF: 0.228 AC: 9482 AN: 41516

American (AMR) AF: 0.146 AC: 2231 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.184 AC: 639 AN: 3470

East Asian (EAS) AF: 0.0187 AC: 97 AN: 5188

South Asian (SAS) AF: 0.266 AC: 1281 AN: 4818

European-Finnish (FIN) AF: 0.256 AC: 2702 AN: 10574

Middle Eastern (MID) AF: 0.264 AC: 77 AN: 292

European-Non Finnish (NFE) AF: 0.241 AC: 16364 AN: 67988

Other (OTH) AF: 0.208 AC: 439 AN: 2114

Alfa AF: 0.228 Hom.: 13494

Bravo AF: 0.209

Asia WGS AF: 0.176 AC: 614 AN: 3478

EpiCase AF: 0.232

EpiControl AF: 0.227

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	1	Cone-rod dystrophy 13 (1)
-	-	1	Leber congenital amaurosis 6 (1)
-	-	1	Leber congenital amaurosis 6;C2750720:Cone-rod dystrophy 13 (1)
-	-	1	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_noAF	Benign	-0.75
CADD	Benign	6.9
DANN	Benign	0.86
PhyloP100		-0.37
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs9322965; hg19: chr14-21792811; COSMIC: COSV99251668; COSMIC: COSV99251668;