chrX-38269709-C-T

Position:

chrX-38269709-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000339363.7(RPGR):c.2980G>A(p.Asp994Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000197 in 1,206,564 control chromosomes in the GnomAD database, including 2 homozygotes. There are 62 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D994V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00085 ( 1 hom., 18 hem., cov: 22)

Exomes 𝑓: 0.00013 ( 1 hom. 44 hem. )

Consequence

RPGR
ENST00000339363.7 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.01

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0052778423).

BP6

Variant X-38269709-C-T is Benign according to our data. Variant chrX-38269709-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 454516.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-38269709-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000845 (94/111223) while in subpopulation AFR AF= 0.003 (92/30652). AF 95% confidence interval is 0.00251. There are 1 homozygotes in gnomad4. There are 18 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd4 at 18 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons
RPGR	NM_000328.3 linkuse as main transcript	c.2365G>A	p.Asp789Asn	missense_variant	19/19
RPGR	NM_001367245.1 linkuse as main transcript	c.2362G>A	p.Asp788Asn	missense_variant	19/19
RPGR	NM_001367246.1 linkuse as main transcript	c.2179G>A	p.Asp727Asn	missense_variant	18/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	Appris	UniProt
RPGR	ENST00000339363.7 linkuse as main transcript	c.2980G>A	p.Asp994Asn	missense_variant	18/18	5	P4	Q92834-1
RPGR	ENST00000642395.2 linkuse as main transcript	c.2365G>A	p.Asp789Asn	missense_variant	19/19		A2	Q92834-2
RPGR	ENST00000644337.1 linkuse as main transcript	c.2179G>A	p.Asp727Asn	missense_variant	18/18			Q92834-4

Frequencies

GnomAD3 genomes

AF:

0.000837

AC:

AN:

111172

Hom.:

Cov.:

AF XY:

0.000539

AC XY:

AN XY:

33388

show subpopulations

Gnomad AFR

AF:

0.00298

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000191

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000202

AC:

AN:

183326

Hom.:

AF XY:

0.0000885

AC XY:

AN XY:

67810

show subpopulations

Gnomad AFR exome

AF:

0.00259

Gnomad AMR exome

AF:

0.000109

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS 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:

0.000131

AC:

144

AN:

1095341

Hom.:

Cov.:

AF XY:

0.000122

AC XY:

AN XY:

360817

show subpopulations

Gnomad4 AFR exome

AF:

0.00402

Gnomad4 AMR exome

AF:

0.000170

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000185

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000143

Gnomad4 OTH exome

AF:

0.000413

GnomAD4 genome

AF:

0.000845

AC:

AN:

111223

Hom.:

Cov.:

AF XY:

0.000538

AC XY:

AN XY:

33449

show subpopulations

Gnomad4 AFR

AF:

0.00300

Gnomad4 AMR

AF:

0.000191

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000858

Hom.:

Bravo

AF:

0.000971

ESP6500AA

AF:

0.00183

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000214

AC:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 14, 2021	This alteration is classified as likely 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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.89

BayesDel_noAF

Benign

-1.1

CADD

Benign

0.13

DANN

Benign

0.76

DEOGEN2

Benign

0.019

.;.;T;.;.

FATHMM_MKL

Benign

0.00031

LIST_S2

Benign

0.41

.;T;T;T;T

M_CAP

Benign

0.0037

MetaRNN

Benign

0.0053

T;T;T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

-0.51

.;.;N;.;.

MutationTaster

Benign

1.0

N;N;N;N

PROVEAN

Benign

0.83

N;.;N;.;.

REVEL

Benign

0.047

Sift

Benign

1.0

T;.;T;.;.

Sift4G

Benign

1.0

T;.;T;.;.

Polyphen

0.0010

B;B;.;.;.

Vest4

0.056

MVP

0.068

ClinPred

0.00034

GERP RS

1.2

Varity_R

0.037

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over