rs80178653

Variant names:

• chrX-38301222-A-G
• rs80178653
• NM_001034853.2:c.1059+25T>C

Variant summary

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

The NM_001034853.2(RPGR):​c.1059+25T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0339 in 1,157,980 control chromosomes in the GnomAD database, including 1,207 homozygotes. There are 13,490 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.031 (92 hom., 1209 hem., cov: 22)
  • Exomes 𝑓: 0.034 (1115 hom. 12281 hem.)
• Consequence: RPGR NM_001034853.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.684
• Publications: 2 publications found

Genes affected

RPGR (HGNC:10295): (retinitis pigmentosa GTPase regulator) This gene encodes a protein with a series of six RCC1-like domains (RLDs), characteristic of the highly conserved guanine nucleotide exchange factors. The encoded protein is found in the Golgi body and interacts with RPGRIP1. This protein localizes to the outer segment of rod photoreceptors and is essential for their viability. Mutations in this gene have been associated with X-linked retinitis pigmentosa (XLRP). Multiple alternatively spliced transcript variants that encode different isoforms of this gene have been reported, but the full-length natures of only some have been determined. [provided by RefSeq, Dec 2008]

RPGR Gene-Disease associations (from GenCC):

• retinitis pigmentosa 3

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• RPGR-related retinopathy

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• primary ciliary dyskinesia-retinitis pigmentosa syndrome

  Inheritance: XL Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• cone-rod dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• retinitis pigmentosa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• macular degeneration, X-linked atrophic

  Inheritance: XL Classification: LIMITED Submitted by: G2P

ENSG00000250349 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant X-38301222-A-G is Benign according to our data. Variant chrX-38301222-A-G is described in ClinVar as Benign. ClinVar VariationId is 257191.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.129 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001034853.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPGR	NM_001034853.2	MANE Select	c.1059+25T>C		intron	N/A	NP_001030025.1
	RPGR	NM_000328.3		c.1059+25T>C		intron	N/A	NP_000319.1
	RPGR	NM_001367245.1		c.1056+25T>C		intron	N/A	NP_001354174.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPGR	ENST00000645032.1	MANE Select	c.1059+25T>C		intron	N/A	ENSP00000495537.1
	ENSG00000250349	ENST00000465127.1	TSL:5	c.172-364899A>G		intron	N/A	ENSP00000417050.1
	RPGR	ENST00000494841.1	TSL:1	n.322+25T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0312 AC: 3480 AN: 111660 Hom.: 93 Cov.: 22

Gnomad AFR AF: 0.00861

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0939

Gnomad ASJ AF: 0.0257

Gnomad EAS AF: 0.0723

Gnomad SAS AF: 0.141

Gnomad FIN AF: 0.0734

Gnomad MID AF: 0.0169

Gnomad NFE AF: 0.0196

Gnomad OTH AF: 0.0353

GnomAD2 exomes AF: 0.0712 AC: 11344 AN: 159227 AF XY: 0.0669

Gnomad AFR exome AF: 0.00854

Gnomad AMR exome AF: 0.213

Gnomad ASJ exome AF: 0.0189

Gnomad EAS exome AF: 0.0701

Gnomad FIN exome AF: 0.0752

Gnomad NFE exome AF: 0.0193

Gnomad OTH exome AF: 0.0387

GnomAD4 exome AF: 0.0342 AC: 35808 AN: 1046264 Hom.: 1115 Cov.: 23 AF XY: 0.0378 AC XY: 12281 AN XY: 324502

African (AFR) AF: 0.00837 AC: 210 AN: 25099

American (AMR) AF: 0.197 AC: 6691 AN: 33901

Ashkenazi Jewish (ASJ) AF: 0.0190 AC: 359 AN: 18904

East Asian (EAS) AF: 0.0784 AC: 2313 AN: 29515

South Asian (SAS) AF: 0.143 AC: 7337 AN: 51183

European-Finnish (FIN) AF: 0.0692 AC: 2745 AN: 39650

Middle Eastern (MID) AF: 0.0209 AC: 82 AN: 3918

European-Non Finnish (NFE) AF: 0.0182 AC: 14575 AN: 799754

Other (OTH) AF: 0.0337 AC: 1496 AN: 44340

GnomAD4 genome AF: 0.0312 AC: 3483 AN: 111716 Hom.: 92 Cov.: 22 AF XY: 0.0357 AC XY: 1209 AN XY: 33900

African (AFR) AF: 0.00859 AC: 265 AN: 30841

American (AMR) AF: 0.0941 AC: 984 AN: 10455

Ashkenazi Jewish (ASJ) AF: 0.0257 AC: 68 AN: 2651

East Asian (EAS) AF: 0.0726 AC: 258 AN: 3555

South Asian (SAS) AF: 0.141 AC: 372 AN: 2638

European-Finnish (FIN) AF: 0.0734 AC: 439 AN: 5982

Middle Eastern (MID) AF: 0.0139 AC: 3 AN: 216

European-Non Finnish (NFE) AF: 0.0196 AC: 1041 AN: 53166

Other (OTH) AF: 0.0348 AC: 53 AN: 1523

Alfa AF: 0.0235 Hom.: 184

Bravo AF: 0.0350

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	7.8
DANN	Benign	0.88
PhyloP100		0.68
PromoterAI		-0.00010	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs80178653; hg19: chrX-38160475;