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rs368434311

chr14-21324775-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6BP7

The NM_020366.4(RPGRIP1):c.1920C>T(p.Ala640=) 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

Scores

2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:5

Conservation

PhyloP100: -0.614
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PM2
?
    PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Very rare variant in population databases, with high coverage;
BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.55).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
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
?
    BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=-0.614 with no splicing effect.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
RPGRIP1NM_020366.4 linkuse as main transcriptc.1920C>T p.Ala640= synonymous_variant 15/25 ENST00000400017.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
RPGRIP1ENST00000400017.7 linkuse as main transcriptc.1920C>T p.Ala640= synonymous_variant 15/251 NM_020366.4 P2Q96KN7-1

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.000276
AC:
42
AN:
152220
Hom.:
0
Cov.:
32
show subpopulations
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
show subpopulations
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
show subpopulations
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
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.000276
AC:
42
AN:
152338
Hom.:
0
Cov.:
32
AF XY:
0.000215
AC XY:
16
AN XY:
74496
show subpopulations
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:2Benign:5
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Cone-rod dystrophy 13 Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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. -
Likely benign, criteria provided, single submitterclinical testingGenome-Nilou LabNov 07, 2021- -
Leber congenital amaurosis 6 Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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. -
Likely benign, criteria provided, single submitterclinical testingGenome-Nilou LabNov 07, 2021- -
not specified Benign:1
Likely benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Leber congenital amaurosis 6;C2750720:Cone-rod dystrophy 13 Benign:1
Likely benign, criteria provided, single submitterclinical testingInvitaeJan 12, 2024- -
not provided Benign:1
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenJul 01, 2023RPGRIP1: 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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs368434311; hg19: chr14-21792934; API