rs113968324

Variant names:

• chrX-38269709-C-G
• rs113968324
• ENST00000465127.1:c.172-396412C>G

Your query was ambiguous. Multiple possible variants found:

• chrX-38269709-C-G
• chrX-38269709-C-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_000328.3(RPGR):​c.2365G>C​(p.Asp789His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000746 in 1,206,513 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D789N) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., 0 hem., cov: 22)
  • Exomes 𝑓: 0.0000064 (0 hom. 3 hem.)
• Consequence: RPGR NM_000328.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.01
• Publications: 1 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), PanelApp Australia
• RPGR-related retinopathy

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

  Inheritance: XL Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.113357574).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000328.3. 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
	RPGR	NM_000328.3		c.2365G>C	p.Asp789His	missense	Exon 19 of 19	NP_000319.1	Q92834-2
	RPGR	NM_001367245.1		c.2362G>C	p.Asp788His	missense	Exon 19 of 19	NP_001354174.1
	RPGR	NM_001367246.1		c.2179G>C	p.Asp727His	missense	Exon 18 of 18	NP_001354175.1	Q92834-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENSG00000250349	ENST00000465127.1	TSL:5	c.172-396412C>G		intron	N/A	ENSP00000417050.1	B4E171
	RPGR	ENST00000339363.7	TSL:5	c.2980G>C	p.Asp994His	missense	Exon 18 of 18	ENSP00000343671.3	Q92834-1
	RPGR	ENST00000642395.2		c.2365G>C	p.Asp789His	missense	Exon 19 of 19	ENSP00000493468.2	Q92834-2

Frequencies

GnomAD3 genomes AF: 0.0000180 AC: 2 AN: 111172 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000377

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000639 AC: 7 AN: 1095341 Hom.: 0 Cov.: 28 AF XY: 0.00000831 AC XY: 3 AN XY: 360817

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 26356

American (AMR) AF: 0.00 AC: 0 AN: 35201

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 30164

South Asian (SAS) AF: 0.00 AC: 0 AN: 54065

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40483

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4126

European-Non Finnish (NFE) AF: 0.00000834 AC: 7 AN: 839595

Other (OTH) AF: 0.00 AC: 0 AN: 45988

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000281198), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000180 AC: 2 AN: 111172 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 33388

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 30584

American (AMR) AF: 0.00 AC: 0 AN: 10451

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2635

East Asian (EAS) AF: 0.00 AC: 0 AN: 3568

South Asian (SAS) AF: 0.00 AC: 0 AN: 2644

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5827

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 236

European-Non Finnish (NFE) AF: 0.0000377 AC: 2 AN: 53053

Other (OTH) AF: 0.00 AC: 0 AN: 1491

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 7

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Primary ciliary dyskinesia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.86
CADD	Benign	7.9
DANN	Benign	0.66
DEOGEN2	Benign	0.035	T
FATHMM_MKL	Benign	0.057	N
LIST_S2	Benign	0.45	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N
PhyloP100		1.0
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.11
Sift	Benign	0.043	D
Sift4G	Uncertain	0.034	D
Polyphen		0.85	P
Vest4		0.092
MutPred		0.15		Loss of loop (P = 0.0288)
MVP		0.068
ClinPred		0.25	T
GERP RS		1.2
Varity_R		0.084
Mutation Taster		=94/6	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: rs113968324; hg19: chrX-38128962;