rs768169831

Variant names:

• chrX-38287906-T-C
• rs768169831
• NM_001034853.2:c.1708A>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001034853.2(RPGR):​c.1708A>G​(p.Thr570Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000282 in 1,097,412 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 17 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T570M) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.000028 (0 hom. 17 hem.)
• Consequence: RPGR NM_001034853.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -0.251
• 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.038601905).
• BP6: Variant X-38287906-T-C is Benign according to our data. Variant chrX-38287906-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 414013.
• BS2: High AC in GnomAdExome4 at 31 XL,AD gene.

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.1708A>G	p.Thr570Ala	missense	Exon 14 of 15	NP_001030025.1
	RPGR	NM_000328.3		c.1708A>G	p.Thr570Ala	missense	Exon 14 of 19	NP_000319.1
	RPGR	NM_001367245.1		c.1705A>G	p.Thr569Ala	missense	Exon 14 of 19	NP_001354174.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPGR	ENST00000645032.1	MANE Select	c.1708A>G	p.Thr570Ala	missense	Exon 14 of 15	ENSP00000495537.1
	ENSG00000250349	ENST00000465127.1	TSL:5	c.172-378215T>C		intron	N/A	ENSP00000417050.1
	RPGR	ENST00000339363.7	TSL:5	c.1708A>G	p.Thr570Ala	missense	Exon 14 of 18	ENSP00000343671.3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.000115 AC: 21 AN: 182608 AF XY: 0.000134

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000512

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000282 AC: 31 AN: 1097412 Hom.: 0 Cov.: 31 AF XY: 0.0000469 AC XY: 17 AN XY: 362832

African (AFR) AF: 0.00 AC: 0 AN: 26374

American (AMR) AF: 0.000455 AC: 16 AN: 35145

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19352

East Asian (EAS) AF: 0.00 AC: 0 AN: 30196

South Asian (SAS) AF: 0.000259 AC: 14 AN: 53968

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40486

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4132

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 841689

Other (OTH) AF: 0.0000217 AC: 1 AN: 46070

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000529

ExAC AF: 0.0000988 AC: 12

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Primary ciliary dyskinesia Benign:2

Jan 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 12, 2024

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

not provided Uncertain:1

Dec 01, 2020

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

X-linked cone-rod dystrophy 1;C1845667:Retinitis pigmentosa 3;C2749137:Retinitis pigmentosa, X-linked, and sinorespiratory infections, with or without deafness;C3151784:Macular degeneration, X-linked atrophic Benign:1

Oct 14, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.13
DANN	Benign	0.49
DEOGEN2	Benign	0.038	T
FATHMM_MKL	Benign	0.028	N
LIST_S2	Benign	0.32	T
M_CAP	Benign	0.0059	T
MetaRNN	Benign	0.039	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	N
PhyloP100		-0.25
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.99	N
REVEL	Benign	0.044
Sift	Benign	0.14	T
Sift4G	Benign	0.70	T
Polyphen		0.79	P
Vest4		0.042
MutPred		0.18		Gain of sheet (P = 0.0827)
MVP		0.17
MPC		0.021
ClinPred		0.028	T
GERP RS		-1.7
Varity_R		0.032
gMVP		0.034
Mutation Taster		=98/2	polymorphism

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: rs768169831; hg19: chrX-38147159;