NM_020366.4:c.525A>G

Variant names:

• chr14-21302522-A-G
• rs17792599
• NM_020366.4:c.525A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_020366.4(RPGRIP1):​c.525A>G​(p.Pro175Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.171 in 1,583,980 control chromosomes in the GnomAD database, including 25,153 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2146 hom., cov: 33)
  • Exomes 𝑓: 0.17 (23007 hom.)
• Consequence: RPGRIP1 NM_020366.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: -1.77
• Publications: 21 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 14-21302522-A-G is Benign according to our data. Variant chr14-21302522-A-G is described in ClinVar as Benign. ClinVar VariationId is 99826.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.77 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.177 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.525A>G	p.Pro175Pro	synonymous	Exon 5 of 25	NP_065099.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPGRIP1	ENST00000400017.7	TSL:1 MANE Select	c.525A>G	p.Pro175Pro	synonymous	Exon 5 of 25	ENSP00000382895.2	Q96KN7-1
	RPGRIP1	ENST00000557771.5	TSL:5	c.525A>G	p.Pro175Pro	synonymous	Exon 4 of 24	ENSP00000451219.1	G3V3F7
	RPGRIP1	ENST00000556336.5	TSL:5	c.525A>G	p.Pro175Pro	synonymous	Exon 4 of 21	ENSP00000450445.1	G3V236

Frequencies

GnomAD3 genomes AF: 0.159 AC: 24213 AN: 152084 Hom.: 2146 Cov.: 33

Gnomad AFR AF: 0.128

Gnomad AMI AF: 0.231

Gnomad AMR AF: 0.162

Gnomad ASJ AF: 0.381

Gnomad EAS AF: 0.0862

Gnomad SAS AF: 0.113

Gnomad FIN AF: 0.109

Gnomad MID AF: 0.266

Gnomad NFE AF: 0.180

Gnomad OTH AF: 0.212

GnomAD2 exomes AF: 0.157 AC: 35780 AN: 227846 AF XY: 0.158

Gnomad AFR exome AF: 0.128

Gnomad AMR exome AF: 0.111

Gnomad ASJ exome AF: 0.393

Gnomad EAS exome AF: 0.0941

Gnomad FIN exome AF: 0.106

Gnomad NFE exome AF: 0.183

Gnomad OTH exome AF: 0.200

GnomAD4 exome AF: 0.173 AC: 247211 AN: 1431778 Hom.: 23007 Cov.: 30 AF XY: 0.172 AC XY: 122457 AN XY: 710066

African (AFR) AF: 0.128 AC: 4228 AN: 33056

American (AMR) AF: 0.118 AC: 5024 AN: 42580

Ashkenazi Jewish (ASJ) AF: 0.395 AC: 10011 AN: 25314

East Asian (EAS) AF: 0.0866 AC: 3386 AN: 39118

South Asian (SAS) AF: 0.119 AC: 9644 AN: 80970

European-Finnish (FIN) AF: 0.106 AC: 5528 AN: 51920

Middle Eastern (MID) AF: 0.252 AC: 1433 AN: 5682

European-Non Finnish (NFE) AF: 0.180 AC: 196758 AN: 1094082

Other (OTH) AF: 0.190 AC: 11199 AN: 59056

GnomAD4 genome AF: 0.159 AC: 24214 AN: 152202 Hom.: 2146 Cov.: 33 AF XY: 0.154 AC XY: 11441 AN XY: 74416

African (AFR) AF: 0.127 AC: 5289 AN: 41532

American (AMR) AF: 0.162 AC: 2470 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.381 AC: 1321 AN: 3470

East Asian (EAS) AF: 0.0868 AC: 449 AN: 5174

South Asian (SAS) AF: 0.113 AC: 547 AN: 4822

European-Finnish (FIN) AF: 0.109 AC: 1155 AN: 10602

Middle Eastern (MID) AF: 0.265 AC: 78 AN: 294

European-Non Finnish (NFE) AF: 0.180 AC: 12254 AN: 68016

Other (OTH) AF: 0.208 AC: 441 AN: 2116

Alfa AF: 0.183 Hom.: 6469

Bravo AF: 0.165

Asia WGS AF: 0.0970 AC: 340 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (3)
-	-	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 specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	2.5
DANN	Benign	0.34
PhyloP100		-1.8
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs17792599; hg19: chr14-21770681; COSMIC: COSV52850162;