X-38322955-G-C

Variant names:

• chrX-38322955-G-C
• rs757403373
• NM_001034853.2:c.155-10C>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001034853.2(RPGR):​c.155-10C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000432 in 1,156,118 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000090 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.0000038 (0 hom. 2 hem.)
• Consequence: RPGR NM_001034853.2 intron
• Scores: Splicing: ADA: 0.0001692
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.467
• 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BS2: High Hemizygotes in GnomAdExome4 at 2 XL,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPGR	NM_001034853.2	c.155-10C>G		intron_variant	Intron 2 of 14	ENST00000645032.1	NP_001030025.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPGR	ENST00000645032.1	c.155-10C>G		intron_variant	Intron 2 of 14		NM_001034853.2	ENSP00000495537.1
ENSG00000250349	ENST00000465127.1	c.172-343166G>C		intron_variant	Intron 3 of 8	5		ENSP00000417050.1

Frequencies

GnomAD3 genomes AF: 0.00000895 AC: 1 AN: 111711 Hom.: 0 Cov.: 23

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: 0.0000188

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000383 AC: 4 AN: 1044407 Hom.: 0 Cov.: 24 AF XY: 0.00000630 AC XY: 2 AN XY: 317503

African (AFR) AF: 0.00 AC: 0 AN: 25403

American (AMR) AF: 0.00 AC: 0 AN: 35145

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19072

East Asian (EAS) AF: 0.00 AC: 0 AN: 29924

South Asian (SAS) AF: 0.00 AC: 0 AN: 52907

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40507

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3999

European-Non Finnish (NFE) AF: 0.00000504 AC: 4 AN: 793076

Other (OTH) AF: 0.00 AC: 0 AN: 44374

GnomAD4 genome AF: 0.00000895 AC: 1 AN: 111711 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 33923

⚠️ 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: 30746

American (AMR) AF: 0.00 AC: 0 AN: 10503

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 3599

South Asian (SAS) AF: 0.00 AC: 0 AN: 2723

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5948

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

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53124

Other (OTH) AF: 0.00 AC: 0 AN: 1512

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 2

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.19
DANN	Benign	0.55
PhyloP100		0.47

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00017
dbscSNV1_RF	Benign	0.0040
SpliceAI score (max)		0.19		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: rs757403373; hg19: chrX-38182208;