ENST00000465127.1:c.172-396349G>T

Variant names:

• chrX-38269772-G-T
• rs34117835
• ENST00000465127.1:c.172-396349G>T

Variant summary

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

The ENST00000465127.1(ENSG00000250349):​c.172-396349G>T variant causes a intron change. The variant allele was found at a frequency of 0.00475 in 1,207,676 control chromosomes in the GnomAD database, including 192 homozygotes. There are 1,489 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (91 hom., 704 hem., cov: 23)
  • Exomes 𝑓: 0.0027 (101 hom. 785 hem.)
• Consequence: ENSG00000250349 ENST00000465127.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 4.87
• Publications: 3 publications found

Genes affected

ENSG00000250349 (HGNC:):

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018976331).
• BP6: Variant X-38269772-G-T is Benign according to our data. Variant chrX-38269772-G-T is described in ClinVar as Benign. ClinVar VariationId is 255835.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0827 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000465127.1. 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_000328.3		c.2302C>A	p.Pro768Thr	missense	Exon 19 of 19	NP_000319.1
	RPGR	NM_001367245.1		c.2299C>A	p.Pro767Thr	missense	Exon 19 of 19	NP_001354174.1
	RPGR	NM_001367246.1		c.2116C>A	p.Pro706Thr	missense	Exon 18 of 18	NP_001354175.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENSG00000250349	ENST00000465127.1	TSL:5	c.172-396349G>T		intron	N/A	ENSP00000417050.1
	RPGR	ENST00000339363.7	TSL:5	c.2917C>A	p.Pro973Thr	missense	Exon 18 of 18	ENSP00000343671.3
	RPGR	ENST00000642395.2		c.2302C>A	p.Pro768Thr	missense	Exon 19 of 19	ENSP00000493468.2

Frequencies

GnomAD3 genomes AF: 0.0249 AC: 2766 AN: 111229 Hom.: 91 Cov.: 23

Gnomad AFR AF: 0.0856

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0116

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000375

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000283

Gnomad OTH AF: 0.0140

GnomAD2 exomes AF: 0.00726 AC: 1325 AN: 182556 AF XY: 0.00413

Gnomad AFR exome AF: 0.0889

Gnomad AMR exome AF: 0.00468

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000221

Gnomad OTH exome AF: 0.00378

GnomAD4 exome AF: 0.00271 AC: 2973 AN: 1096396 Hom.: 101 Cov.: 29 AF XY: 0.00217 AC XY: 785 AN XY: 361928

African (AFR) AF: 0.0913 AC: 2405 AN: 26351

American (AMR) AF: 0.00557 AC: 196 AN: 35191

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19363

East Asian (EAS) AF: 0.00 AC: 0 AN: 30168

South Asian (SAS) AF: 0.000166 AC: 9 AN: 54070

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40269

Middle Eastern (MID) AF: 0.00412 AC: 17 AN: 4126

European-Non Finnish (NFE) AF: 0.000112 AC: 94 AN: 840824

Other (OTH) AF: 0.00547 AC: 252 AN: 46034

GnomAD4 genome AF: 0.0248 AC: 2765 AN: 111280 Hom.: 91 Cov.: 23 AF XY: 0.0210 AC XY: 704 AN XY: 33522

African (AFR) AF: 0.0854 AC: 2607 AN: 30521

American (AMR) AF: 0.0116 AC: 121 AN: 10468

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2641

East Asian (EAS) AF: 0.00 AC: 0 AN: 3571

South Asian (SAS) AF: 0.000376 AC: 1 AN: 2658

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5933

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.000283 AC: 15 AN: 53068

Other (OTH) AF: 0.0139 AC: 21 AN: 1515

Alfa AF: 0.00903 Hom.: 418

Bravo AF: 0.0297

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0890 AC: 341

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.00832 AC: 1010

EpiCase AF: 0.000382

EpiControl AF: 0.000832

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	18
DANN	Benign	0.95
DEOGEN2	Benign	0.092	T
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.76	T
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L
PhyloP100		4.9
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.071
Sift	Benign	0.19	T
Sift4G	Benign	0.063	T
Polyphen		0.85	P
Vest4		0.19
MVP		0.19
ClinPred		0.044	T
GERP RS		3.3
Varity_R		0.075
Mutation Taster		=97/3	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: rs34117835; hg19: chrX-38129025;