X-38291470-C-T

Variant names:

• chrX-38291470-C-T
• rs1555962965
• NM_001034853.2:c.1429G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001034853.2(RPGR):​c.1429G>A​(p.Glu477Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000974 in 1,026,684 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.7e-7 (0 hom. 0 hem.)
• Consequence: RPGR NM_001034853.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.17
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.038778007).

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.1429G>A	p.Glu477Lys	missense	Exon 12 of 15	NP_001030025.1
	RPGR	NM_000328.3		c.1429G>A	p.Glu477Lys	missense	Exon 12 of 19	NP_000319.1
	RPGR	NM_001367245.1		c.1426G>A	p.Glu476Lys	missense	Exon 12 of 19	NP_001354174.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPGR	ENST00000645032.1	MANE Select	c.1429G>A	p.Glu477Lys	missense	Exon 12 of 15	ENSP00000495537.1
	ENSG00000250349	ENST00000465127.1	TSL:5	c.172-374651C>T		intron	N/A	ENSP00000417050.1
	RPGR	ENST00000339363.7	TSL:5	c.1429G>A	p.Glu477Lys	missense	Exon 12 of 18	ENSP00000343671.3

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 9.74e-7 AC: 1 AN: 1026684 Hom.: 0 Cov.: 21 AF XY: 0.00 AC XY: 0 AN XY: 307860

African (AFR) AF: 0.00 AC: 0 AN: 25145

American (AMR) AF: 0.00 AC: 0 AN: 35082

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18873

East Asian (EAS) AF: 0.0000336 AC: 1 AN: 29725

South Asian (SAS) AF: 0.00 AC: 0 AN: 52382

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38460

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3953

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 779351

Other (OTH) AF: 0.00 AC: 0 AN: 43713

GnomAD4 genome Cov.: 22

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.93
CADD	Benign	1.7
DANN	Benign	0.27
DEOGEN2	Benign	0.019	T
FATHMM_MKL	Benign	0.041	N
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.0060	T
MetaRNN	Benign	0.039	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.88	N
PhyloP100		1.2
PrimateAI	Benign	0.34	T
PROVEAN	Benign	1.1	N
REVEL	Benign	0.053
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.021	B
Vest4		0.078
MutPred		0.33		Gain of ubiquitination at E477 (P = 0)
MVP		0.068
MPC		0.022
ClinPred		0.037	T
GERP RS		-2.5
Varity_R		0.045
gMVP		0.15
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs1555962965; hg19: chrX-38150723;