Genetic Variant ENSG00000250349:c.172-396412C>T (chrX-38269709-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000328.3(RPGR):c.2365G>A(p.Asp789Asn) 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. 14/19 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. D789H) 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
NM_000328.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.01

Publications

1 publications found

Variant links:

Genes affected

ENSG00000250349 (HGNC:):

ENSG00000250349 links:

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

RPGR links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 454516.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.

BS2

High AC in GnomAd4 at 94 XL,AD gene.

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

Gene	Transcript	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RPGR	NM_000328.3	c.2365G>A	p.Asp789Asn	missense	Exon 19 of 19	NP_000319.1	Q92834-2
RPGR	NM_001367245.1	c.2362G>A	p.Asp788Asn	missense	Exon 19 of 19	NP_001354174.1
RPGR	NM_001367246.1	c.2179G>A	p.Asp727Asn	missense	Exon 18 of 18	NP_001354175.1	Q92834-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ENSG00000250349	ENST00000465127.1	TSL:5	c.172-396412C>T		intron	N/A	ENSP00000417050.1	B4E171
RPGR	ENST00000339363.7	TSL:5	c.2980G>A	p.Asp994Asn	missense	Exon 18 of 18	ENSP00000343671.3	Q92834-1
RPGR	ENST00000642395.2		c.2365G>A	p.Asp789Asn	missense	Exon 19 of 19	ENSP00000493468.2	Q92834-2

Frequencies

GnomAD3 genomes

AF:

0.000837

AC:

AN:

111172

Hom.:

Cov.:

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

GnomAD2 exomes

AF:

0.000202

AC:

AN:

183326

AF XY:

0.0000885

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 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

African (AFR)

AF:

0.00402

AC:

106

AN:

26356

American (AMR)

AF:

0.000170

AC:

AN:

35201

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19363

East Asian (EAS)

AF:

0.00

AC:

AN:

30164

South Asian (SAS)

AF:

0.0000185

AC:

AN:

54065

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40483

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4126

European-Non Finnish (NFE)

AF:

0.0000143

AC:

AN:

839595

Other (OTH)

AF:

0.000413

AC:

AN:

45988

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000845

AC:

AN:

111223

Hom.:

Cov.:

AF XY:

0.000538

AC XY:

AN XY:

33449

show subpopulations

African (AFR)

AF:

0.00300

AC:

AN:

30652

American (AMR)

AF:

0.000191

AC:

AN:

10464

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2635

East Asian (EAS)

AF:

0.00

AC:

AN:

3557

South Asian (SAS)

AF:

0.00

AC:

AN:

2635

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5827

Middle Eastern (MID)

AF:

0.00

AC:

AN:

215

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53045

Other (OTH)

AF:

0.00

AC:

AN:

1510

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000298

Hom.:

Bravo

AF:

0.000971

ESP6500AA

AF:

0.00183

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000214

AC:

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Primary ciliary dyskinesia (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.89

BayesDel_noAF

Benign

-1.1

CADD

Benign

0.13

(source)

DANN

Benign

0.76

DEOGEN2

Benign

0.019

FATHMM_MKL

Benign

0.00031

LIST_S2

Benign

0.41

M_CAP

Benign

0.0037

MetaRNN

Benign

0.0053

MetaSVM

Benign

-0.98

MutationAssessor

Benign

-0.51

PhyloP100

1.0

PROVEAN

Benign

0.83

REVEL

Benign

0.047

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0010

Vest4

0.056

MVP

0.068

ClinPred

0.00034

GERP RS

1.2

Varity_R

0.037

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over