rs7157052

Variant names:

• chr14-21325077-G-A
• rs7157052
• NM_020366.4:c.2215+7G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_020366.4(RPGRIP1):​c.2215+7G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.215 in 1,599,062 control chromosomes in the GnomAD database, including 38,971 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3235 hom., cov: 32)
  • Exomes 𝑓: 0.22 (35736 hom.)
• Consequence: RPGRIP1 NM_020366.4 splice_region, intron
• Scores: Splicing: ADA: 0.00001395
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.875
• Publications: 12 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 14-21325077-G-A is Benign according to our data. Variant chr14-21325077-G-A is described in ClinVar as Benign. ClinVar VariationId is 261227.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.23 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.2215+7G>A		splice_region intron	N/A	NP_065099.3
	RPGRIP1	NM_001377948.1		c.1141+7G>A		splice_region intron	N/A	NP_001364877.1
	RPGRIP1	NM_001377949.1		c.796+352G>A		intron	N/A	NP_001364878.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPGRIP1	ENST00000400017.7	TSL:1 MANE Select	c.2215+7G>A		splice_region intron	N/A	ENSP00000382895.2	Q96KN7-1
	RPGRIP1	ENST00000555587.5	TSL:1	c.640+7G>A		splice_region intron	N/A	ENSP00000451262.1	G3V3I7
	RPGRIP1	ENST00000382933.8	TSL:1	c.689-2546G>A		intron	N/A	ENSP00000372391.4	Q96KN7-4

Frequencies

GnomAD3 genomes AF: 0.197 AC: 29940 AN: 152070 Hom.: 3235 Cov.: 32

Gnomad AFR AF: 0.173

Gnomad AMI AF: 0.314

Gnomad AMR AF: 0.131

Gnomad ASJ AF: 0.176

Gnomad EAS AF: 0.00539

Gnomad SAS AF: 0.199

Gnomad FIN AF: 0.243

Gnomad MID AF: 0.228

Gnomad NFE AF: 0.233

Gnomad OTH AF: 0.181

GnomAD2 exomes AF: 0.191 AC: 46320 AN: 242254 AF XY: 0.197

Gnomad AFR exome AF: 0.170

Gnomad AMR exome AF: 0.0948

Gnomad ASJ exome AF: 0.190

Gnomad EAS exome AF: 0.00431

Gnomad FIN exome AF: 0.257

Gnomad NFE exome AF: 0.233

Gnomad OTH exome AF: 0.198

GnomAD4 exome AF: 0.217 AC: 313602 AN: 1446874 Hom.: 35736 Cov.: 31 AF XY: 0.217 AC XY: 155901 AN XY: 717886

African (AFR) AF: 0.168 AC: 5536 AN: 33036

American (AMR) AF: 0.101 AC: 4388 AN: 43382

Ashkenazi Jewish (ASJ) AF: 0.181 AC: 4604 AN: 25438

East Asian (EAS) AF: 0.00332 AC: 131 AN: 39420

South Asian (SAS) AF: 0.212 AC: 18073 AN: 85218

European-Finnish (FIN) AF: 0.261 AC: 13811 AN: 53004

Middle Eastern (MID) AF: 0.202 AC: 1150 AN: 5704

European-Non Finnish (NFE) AF: 0.230 AC: 253448 AN: 1102066

Other (OTH) AF: 0.209 AC: 12461 AN: 59606

GnomAD4 genome AF: 0.197 AC: 29959 AN: 152188 Hom.: 3235 Cov.: 32 AF XY: 0.194 AC XY: 14450 AN XY: 74420

African (AFR) AF: 0.173 AC: 7182 AN: 41518

American (AMR) AF: 0.131 AC: 2006 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.176 AC: 611 AN: 3466

East Asian (EAS) AF: 0.00540 AC: 28 AN: 5184

South Asian (SAS) AF: 0.200 AC: 967 AN: 4826

European-Finnish (FIN) AF: 0.243 AC: 2572 AN: 10586

Middle Eastern (MID) AF: 0.221 AC: 65 AN: 294

European-Non Finnish (NFE) AF: 0.233 AC: 15862 AN: 67994

Other (OTH) AF: 0.180 AC: 381 AN: 2116

Alfa AF: 0.214 Hom.: 7408

Bravo AF: 0.185

Asia WGS AF: 0.108 AC: 377 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	Cone-rod dystrophy 13 (1)
-	-	1	Leber congenital amaurosis 6 (1)
-	-	1	Leber congenital amaurosis 6;C2750720:Cone-rod dystrophy 13 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	8.3
DANN	Benign	0.47
PhyloP100		0.88
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000014
dbscSNV1_RF	Benign	0.0020
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: rs7157052; hg19: chr14-21793236; COSMIC: COSV52849042; COSMIC: COSV52849042;