rs34116882

Positions:

• chr14-21345126-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_020366.4(RPGRIP1):​c.3546C>T​(p.Asp1182=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0216 in 1,611,240 control chromosomes in the GnomAD database, including 420 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (24 hom., cov: 32)
  • Exomes 𝑓: 0.022 (396 hom.)
• Consequence: RPGRIP1 NM_020366.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: 0.0360

Genes affected

RPGRIP1 (HGNC:13436): (RPGR interacting protein 1) This gene encodes a photoreceptor protein that interacts with retinitis pigmentosa GTPase regulator protein and is a key component of cone and rod photoreceptor cells. Mutations in this gene lead to autosomal recessive congenital blindness. [provided by RefSeq, Oct 2008]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant 14-21345126-C-T is Benign according to our data. Variant chr14-21345126-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 99820.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-21345126-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.036 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0154 (2344/152256) while in subpopulation NFE AF= 0.0249 (1692/68014). AF 95% confidence interval is 0.0239. There are 24 homozygotes in gnomad4. There are 1103 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 24 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RPGRIP1	NM_020366.4	c.3546C>T	p.Asp1182=	synonymous_variant	23/25	ENST00000400017.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RPGRIP1	ENST00000400017.7	c.3546C>T	p.Asp1182=	synonymous_variant	23/25	1	NM_020366.4	P2

Frequencies

GnomAD3 genomes AF: 0.0154 AC: 2344 AN: 152138 Hom.: 24 Cov.: 32

Gnomad AFR AF: 0.00365

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.00937

Gnomad ASJ AF: 0.0130

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00165

Gnomad FIN AF: 0.0259

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0249

Gnomad OTH AF: 0.00955

GnomAD3 exomes AF: 0.0168 AC: 4173 AN: 249058 Hom.: 46 AF XY: 0.0167 AC XY: 2255 AN XY: 135118

Gnomad AFR exome AF: 0.00271

Gnomad AMR exome AF: 0.00551

Gnomad ASJ exome AF: 0.0138

Gnomad EAS exome AF: 0.0000556

Gnomad SAS exome AF: 0.00180

Gnomad FIN exome AF: 0.0273

Gnomad NFE exome AF: 0.0271

Gnomad OTH exome AF: 0.0157

GnomAD4 exome AF: 0.0222 AC: 32421 AN: 1458984 Hom.: 396 Cov.: 29 AF XY: 0.0218 AC XY: 15798 AN XY: 725938

Gnomad4 AFR exome AF: 0.00335

Gnomad4 AMR exome AF: 0.00550

Gnomad4 ASJ exome AF: 0.0133

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00198

Gnomad4 FIN exome AF: 0.0275

Gnomad4 NFE exome AF: 0.0262

Gnomad4 OTH exome AF: 0.0170

GnomAD4 genome AF: 0.0154 AC: 2344 AN: 152256 Hom.: 24 Cov.: 32 AF XY: 0.0148 AC XY: 1103 AN XY: 74446

Gnomad4 AFR AF: 0.00363

Gnomad4 AMR AF: 0.00936

Gnomad4 ASJ AF: 0.0130

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.0259

Gnomad4 NFE AF: 0.0249

Gnomad4 OTH AF: 0.00945

Alfa AF: 0.0221 Hom.: 16

Bravo AF: 0.0141

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.0233

EpiControl AF: 0.0212

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2 Other:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 31, 2018	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 28, 2023	- -
not provided, no classification provided	literature only	Retina International	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Leber congenital amaurosis 6;C2750720:Cone-rod dystrophy 13 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Cone-rod dystrophy 13 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Leber congenital amaurosis 6 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	5.4
DANN	Benign	0.56

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs34116882; hg19: chr14-21813285;