X-38287904-C-T

Variant names:

• chrX-38287904-C-T
• rs138347728
• NM_001034853.2:c.1710G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001034853.2(RPGR):​c.1710G>A​(p.Thr570Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00042 in 1,209,234 control chromosomes in the GnomAD database, including 2 homozygotes. There are 202 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., 9 hem., cov: 22)
  • Exomes 𝑓: 0.00044 (2 hom. 193 hem.)
• Consequence: RPGR NM_001034853.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.478
• Publications: 1 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), 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

ENSG00000250349 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant X-38287904-C-T is Benign according to our data. Variant chrX-38287904-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 414011.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.478 with no splicing effect.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.00044 (483/1097282) while in subpopulation MID AF = 0.0046 (19/4133). AF 95% confidence interval is 0.00301. There are 2 homozygotes in GnomAdExome4. There are 193 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 25 AD,XL 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPGR	NM_001034853.2	MANE Select	c.1710G>A	p.Thr570Thr	synonymous	Exon 14 of 15	NP_001030025.1	Q92834-6
	RPGR	NM_000328.3		c.1710G>A	p.Thr570Thr	synonymous	Exon 14 of 19	NP_000319.1	Q92834-2
	RPGR	NM_001367245.1		c.1707G>A	p.Thr569Thr	synonymous	Exon 14 of 19	NP_001354174.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPGR	ENST00000645032.1	MANE Select	c.1710G>A	p.Thr570Thr	synonymous	Exon 14 of 15	ENSP00000495537.1	Q92834-6
	ENSG00000250349	ENST00000465127.1	TSL:5	c.172-378217C>T		intron	N/A	ENSP00000417050.1	B4E171
	RPGR	ENST00000339363.7	TSL:5	c.1710G>A	p.Thr570Thr	synonymous	Exon 14 of 18	ENSP00000343671.3	Q92834-1

Frequencies

GnomAD3 genomes AF: 0.000250 AC: 28 AN: 111898 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: 0.00186

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0125

Gnomad NFE AF: 0.000319

Gnomad OTH AF: 0.00198

GnomAD2 exomes AF: 0.000570 AC: 104 AN: 182611 AF XY: 0.000744

Gnomad AFR exome AF: 0.0000760

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000134

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000439

Gnomad NFE exome AF: 0.000441

Gnomad OTH exome AF: 0.00111

GnomAD4 exome AF: 0.000440 AC: 483 AN: 1097282 Hom.: 2 Cov.: 31 AF XY: 0.000532 AC XY: 193 AN XY: 362714

African (AFR) AF: 0.0000379 AC: 1 AN: 26378

American (AMR) AF: 0.00 AC: 0 AN: 35158

Ashkenazi Jewish (ASJ) AF: 0.0000516 AC: 1 AN: 19363

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

South Asian (SAS) AF: 0.00317 AC: 171 AN: 54003

European-Finnish (FIN) AF: 0.000469 AC: 19 AN: 40471

Middle Eastern (MID) AF: 0.00460 AC: 19 AN: 4133

European-Non Finnish (NFE) AF: 0.000285 AC: 240 AN: 841518

Other (OTH) AF: 0.000695 AC: 32 AN: 46062

GnomAD4 genome AF: 0.000223 AC: 25 AN: 111952 Hom.: 0 Cov.: 22 AF XY: 0.000264 AC XY: 9 AN XY: 34126

African (AFR) AF: 0.00 AC: 0 AN: 30824

American (AMR) AF: 0.00 AC: 0 AN: 10549

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2643

East Asian (EAS) AF: 0.00 AC: 0 AN: 3574

South Asian (SAS) AF: 0.00187 AC: 5 AN: 2678

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6014

Middle Eastern (MID) AF: 0.00457 AC: 1 AN: 219

European-Non Finnish (NFE) AF: 0.000319 AC: 17 AN: 53234

Other (OTH) AF: 0.00131 AC: 2 AN: 1531

Alfa AF: 0.000564 Hom.: 4

Bravo AF: 0.000204

EpiCase AF: 0.000545

EpiControl AF: 0.000475

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	Primary ciliary dyskinesia (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.72
DANN	Benign	0.72
PhyloP100		-0.48
Mutation Taster		=100/0	polymorphism (auto)

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: rs138347728; hg19: chrX-38147157; COSMIC: COSV58841388;