rs397514574

Variant names:

• chr2-96287959-C-A
• rs397514574
• NM_014014.5:c.3269G>T

Your query was ambiguous. Multiple possible variants found:

• chr2-96287959-C-A
• chr2-96287959-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5

The NM_014014.5(SNRNP200):​c.3269G>T​(p.Arg1090Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1090Q) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SNRNP200 NM_014014.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.66

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 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
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: 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}.
• 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, 0.992
• PP5: Variant 2-96287959-C-A is Pathogenic according to our data. 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. Variant chr2-96287959-C-A is described in Lovd as [Likely_pathogenic]. Variant chr2-96287959-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SNRNP200	NM_014014.5	c.3269G>T	p.Arg1090Leu	missense_variant	Exon 25 of 45	ENST00000323853.10	NP_054733.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SNRNP200	ENST00000323853.10	c.3269G>T	p.Arg1090Leu	missense_variant	Exon 25 of 45	1	NM_014014.5	ENSP00000317123.5
SNRNP200	ENST00000652267.1	c.3269G>T	p.Arg1090Leu	missense_variant	Exon 27 of 32			ENSP00000498933.1
SNRNP200	ENST00000480615.1	n.386G>T		non_coding_transcript_exon_variant	Exon 5 of 10	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Retinitis pigmentosa 33 Pathogenic:1

Mar 01, 2014

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.70	D
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.59	D
MutationAssessor	Pathogenic	4.4	H
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-6.5	D
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.95		Loss of MoRF binding (P = 0.0051);
MVP		0.88
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		0.97
gMVP		0.94

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: rs397514574; hg19: chr2-96953697;