chr19-40757358-T-A

Position:

• chr19-40757358-T-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_004596.5(SNRPA):​c.100T>A​(p.Phe34Ile) 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 Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 30)
• Consequence: SNRPA NM_004596.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.82

Genes affected

SNRPA (HGNC:11151): (small nuclear ribonucleoprotein polypeptide A) The protein encoded by this gene associates with stem loop II of the U1 small nuclear ribonucleoprotein, which binds the 5' splice site of precursor mRNAs and is required for splicing. The encoded protein autoregulates itself by polyadenylation inhibition of its own pre-mRNA via dimerization and has been implicated in the coupling of splicing and polyadenylation. [provided by RefSeq, Oct 2010]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.959
• PP5: Variant 19-40757358-T-A is Pathogenic according to our data. Variant chr19-40757358-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 446205.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SNRPA	NM_004596.5	c.100T>A	p.Phe34Ile	missense_variant	2/6	ENST00000243563.8	NP_004587.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SNRPA	ENST00000243563.8	c.100T>A	p.Phe34Ile	missense_variant	2/6	1	NM_004596.5	ENSP00000243563	P1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 30

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Spliceosomepathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Laboratorio de Citogenómica y Microarreglos, Universidad Autonoma de Nuevo Leon

Nov 01, 2017

Splicing-related gene mutations might affect in different ways the expression of a single gene or multiple genes. Exome sequencing analyses by Variant Interpreter identified, in independent assays of the patients (two assays in one of them), three homozygous missense variants in exon 2 of SNRPA (hg19; chr19:41,263,260, chr19:41,263,261, and chr19:41,263,263; NM_004596.4). These variants were described as c.97A>G, c.98T>C, and c.100T>A and cause a change in two contiguous amino acids: p.Ile33Ala and p.Phe34Ile. The in-silico analyses (CFSSP, ExPASy web tool) showed a gained rich-α-helix region. Six different bioinformatic platforms predicted a pathogenic consequence for p.Ile33Ala and p.Phe34Ile; however, a more pathogenic score (-8.53, PROVEAN web tool) was predicted when both mutations were analyzed combined. SNRPA encodes for a protein that associates with the stem loop II of the U1 RNA. Thus, SNRPA/U1-A is part of the U1 small nuclear ribonucleoprotein complex. The psychomotor delay/Intellectual disability and growth, eye, craniofacial and hand anomalies in our patients, are features also seen in other spliceosomepathies. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.44	T;.;T;.;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D
MetaSVM	Uncertain	0.44	D
MutationAssessor	Pathogenic	4.7	H;.;.;.;.
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-5.1	D;.;.;.;.
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0020	D;.;.;.;.
Sift4G	Uncertain	0.0030	D;D;D;D;D
Polyphen		0.89	P;.;.;.;.
Vest4		0.87
MutPred		0.85		Loss of catalytic residue at F34 (P = 0.0223);Loss of catalytic residue at F34 (P = 0.0223);Loss of catalytic residue at F34 (P = 0.0223);Loss of catalytic residue at F34 (P = 0.0223);Loss of catalytic residue at F34 (P = 0.0223);
MVP		0.90
MPC		1.8
ClinPred		1.0	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.90
gMVP		0.81

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: rs1555775209; hg19: chr19-41263263;