rs368434311

Variant names:

• chr14-21324775-C-T
• rs368434311
• NM_020366.4:c.1920C>T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PM2 BP4_Strong BP6 BP7 BS1

The NM_020366.4(RPGRIP1):​c.1920C>T​(p.Ala640Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000553 in 1,614,046 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00058 (1 hom.)
• Consequence: RPGRIP1 NM_020366.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:5
• Conservation: PhyloP100: -0.614

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 -8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 14-21324775-C-T is Benign according to our data. Variant chr14-21324775-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 261226.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=2}. Variant chr14-21324775-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.614 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.000582 (850/1461708) while in subpopulation NFE AF= 0.000688 (765/1111868). AF 95% confidence interval is 0.000647. There are 1 homozygotes in gnomad4_exome. There are 412 alleles in male gnomad4_exome subpopulation. Median coverage is 34. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPGRIP1	NM_020366.4	c.1920C>T	p.Ala640Ala	synonymous_variant	Exon 15 of 25	ENST00000400017.7	NP_065099.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPGRIP1	ENST00000400017.7	c.1920C>T	p.Ala640Ala	synonymous_variant	Exon 15 of 25	1	NM_020366.4	ENSP00000382895.2

Frequencies

GnomAD3 genomes AF: 0.000276 AC: 42 AN: 152220 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000514

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000301 AC: 75 AN: 249302 Hom.: 0 AF XY: 0.000296 AC XY: 40 AN XY: 135250

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.0000869

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.000566

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000582 AC: 850 AN: 1461708 Hom.: 1 Cov.: 34 AF XY: 0.000567 AC XY: 412 AN XY: 727138

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000174

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.000688

Gnomad4 OTH exome AF: 0.000977

GnomAD4 genome AF: 0.000276 AC: 42 AN: 152338 Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16 AN XY: 74496

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000514

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000549 Hom.: 0

Bravo AF: 0.000336

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000491

EpiControl AF: 0.000771

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cone-rod dystrophy 13 Uncertain:1 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Nov 07, 2021

Genome-Nilou Lab

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Leber congenital amaurosis 6 Uncertain:1 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Nov 07, 2021

Genome-Nilou Lab

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Jan 13, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Jul 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

RPGRIP1: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	5.5
DANN	Benign	0.58

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

Other links and lift over

dbSNP: rs368434311; hg19: chr14-21792934;