chr2-96287959-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 10P and 5B. PM1PM5PP2PP3_StrongPP5BS1_SupportingBS2

The NM_014014.5(SNRNP200):​c.3269G>A​(p.Arg1090Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000219 in 1,461,864 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1090L) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.000022 ( 0 hom. )

Consequence

SNRNP200
NM_014014.5 missense

Scores

15
3
1

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2

Conservation

PhyloP100: 7.66
Variant links:
Genes affected
SNRNP200 (HGNC:30859): (small nuclear ribonucleoprotein U5 subunit 200) Pre-mRNA splicing is catalyzed by the spliceosome, a complex of specialized RNA and protein subunits that removes introns from a transcribed pre-mRNA segment. The spliceosome consists of small nuclear RNA proteins (snRNPs) U1, U2, U4, U5 and U6, together with approximately 80 conserved proteins. U5 snRNP contains nine specific proteins. This gene encodes one of the U5 snRNP-specific proteins. This protein belongs to the DEXH-box family of putative RNA helicases. It is a core component of U4/U6-U5 snRNPs and appears to catalyze an ATP-dependent unwinding of U4/U6 RNA duplices. Mutations in this gene cause autosomal-dominant retinitis pigmentosa. Alternatively spliced transcript variants encoding different isoforms have been found, but the full-length nature of these variants has not been determined. [provided by RefSeq, Mar 2010]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM1
In a helix (size 26) in uniprot entity U520_HUMAN there are 11 pathogenic changes around while only 0 benign (100%) in NM_014014.5
PM5
Other missense variant is known to change same aminoacid residue: Variant chr2-96287959-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 39746.Status of the report is no_assertion_criteria_provided, 0 stars.
PP2
Missense variant in the SNRNP200 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 14 curated pathogenic missense variants (we use a threshold of 10). The gene has 26 curated benign missense variants. Gene score misZ: 5.9363 (above the threshold of 3.09). Trascript score misZ: 8.7488 (above the threshold of 3.09). GenCC associations: The gene is linked to retinitis pigmentosa 33, SNRNP200-related dominant retinopathy, retinitis pigmentosa.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.989
PP5
Variant 2-96287959-C-T is Pathogenic according to our data. Variant chr2-96287959-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1360981.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Pathogenic=1}. Variant chr2-96287959-C-T is described in Lovd as [Pathogenic]. Variant chr2-96287959-C-T is described in Lovd as [Likely_pathogenic].
BS1
Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.0000219 (32/1461864) while in subpopulation EAS AF= 0.0000504 (2/39698). AF 95% confidence interval is 0.0000183. There are 0 homozygotes in gnomad4_exome. There are 12 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
High AC in GnomAdExome4 at 32 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SNRNP200NM_014014.5 linkc.3269G>A p.Arg1090Gln missense_variant Exon 25 of 45 ENST00000323853.10 NP_054733.2 O75643-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SNRNP200ENST00000323853.10 linkc.3269G>A p.Arg1090Gln missense_variant Exon 25 of 45 1 NM_014014.5 ENSP00000317123.5 O75643-1
SNRNP200ENST00000652267.1 linkc.3269G>A p.Arg1090Gln missense_variant Exon 27 of 32 ENSP00000498933.1 A0A494C1A5
SNRNP200ENST00000480615.1 linkn.386G>A non_coding_transcript_exon_variant Exon 5 of 10 5

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.0000119
AC:
3
AN:
251470
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135910
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000109
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000879
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000219
AC:
32
AN:
1461864
Hom.:
0
Cov.:
32
AF XY:
0.0000165
AC XY:
12
AN XY:
727240
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000504
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000261
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.0000278
Hom.:
0
Bravo
AF:
0.0000113
ExAC
AF:
0.0000247
AC:
3

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Pathogenic:1
Oct 30, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1090 of the SNRNP200 protein (p.Arg1090Gln). This variant is present in population databases (rs397514574, gnomAD 0.01%). This missense change has been observed in individual(s) with autosomal recessive inherited retinal dystrophy (PMID: 29320387). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1360981). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SNRNP200 protein function. For these reasons, this variant has been classified as Pathogenic. -

Retinitis pigmentosa 33 Uncertain:1
Jan 14, 2022
Pangenia Genomics, Pangenia Inc.
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: research

The SNRNP200, c.3269G>A (p.Arg1090Gln) variant is at extremely low frequency in population databases ; allele frequency in East Asia population is 0.0001 by gnomAD v2.1.1. This missense variant results in the amino acid change of p.Arg1090Gln . Another variant resulting in the amino acid change at the same position to a different residue (p.Arg1090Leu ) has been determined to be pathogenic [PMID: 19710410]. In a 4-generation Chinese family with 12 members affected by autosomal dominant retinitis pigmentosa (RP), the heterozygous variant segregated with the disease and was not found in 100 ethnically matched controls. Multiple lines of computational evidence support a deleterious effect on the gene or gene product REVEL=0. 838. There is co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease. This variant has also been detected in a consanguineous Pakistani family [PMID: 29320387 ], co-segregating with an autosomal recessive form of retinitis pigmentosa. -

Retinal dystrophy Uncertain:1
Oct 01, 2023
Dept Of Ophthalmology, Nagoya University
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.24
D
BayesDel_noAF
Pathogenic
0.34
CADD
Pathogenic
29
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.69
D
Eigen
Pathogenic
1.0
Eigen_PC
Pathogenic
0.90
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
1.0
D
M_CAP
Pathogenic
0.68
D
MetaRNN
Pathogenic
0.99
D
MetaSVM
Uncertain
0.69
D
MutationAssessor
Pathogenic
4.4
H
PrimateAI
Pathogenic
0.82
D
PROVEAN
Uncertain
-3.7
D
REVEL
Pathogenic
0.84
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.97
MutPred
0.95
Loss of MoRF binding (P = 0.0179);
MVP
0.89
MPC
2.3
ClinPred
1.0
D
GERP RS
5.3
RBP_binding_hub_radar
0.92
RBP_regulation_power_radar
2.7
Varity_R
0.96
gMVP
0.89

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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: rs397514574; hg19: chr2-96953697; API