rs587776925

Variant names:

• chr1-203863714-G-A
• rs587776925
• NM_003094.4:c.133G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_003094.4(SNRPE):​c.133G>A​(p.Gly45Ser) 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). Synonymous variant affecting the same amino acid position (i.e. G45G) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SNRPE NM_003094.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.59
• Publications: 4 publications found

Genes affected

SNRPE (HGNC:11161): (small nuclear ribonucleoprotein polypeptide E) The protein encoded by this gene is a core component of U small nuclear ribonucleoproteins, which are key components of the pre-mRNA processing spliceosome. The encoded protein plays a role in the 3' end processing of histone transcripts. This protein is one of the targets in the autoimmune disease systemic lupus erythematosus, and mutations in this gene have been associated with hypotrichosis. Several pseudogenes of this gene have been identified. [provided by RefSeq, Jun 2016]

SNRPE Gene-Disease associations (from GenCC):

• hypotrichosis 11

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• hypotrichosis simplex

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.995
• PP5: Variant 1-203863714-G-A is Pathogenic according to our data. Variant chr1-203863714-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 39506.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003094.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SNRPE	NM_003094.4	MANE Select	c.133G>A	p.Gly45Ser	missense	Exon 3 of 5	NP_003085.1
	SNRPE	NM_001328637.2		c.127G>A	p.Gly43Ser	missense	Exon 3 of 5	NP_001315566.1
	SNRPE	NM_001304464.2		c.109G>A	p.Gly37Ser	missense	Exon 3 of 5	NP_001291393.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SNRPE	ENST00000414487.7	TSL:1 MANE Select	c.133G>A	p.Gly45Ser	missense	Exon 3 of 5	ENSP00000400591.2
	SNRPE	ENST00000475035.5	TSL:1	n.234G>A		non_coding_transcript_exon	Exon 3 of 5
	SNRPE	ENST00000367208.1	TSL:2	c.13G>A	p.Gly5Ser	missense	Exon 1 of 3	ENSP00000356176.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Hypotrichosis 11 Pathogenic:1

Jan 10, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.87	D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.69	D
PhyloP100		7.6
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-5.7	D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.015	D
Sift4G	Uncertain	0.016	D
Polyphen		0.94	P
Vest4		0.94
MutPred		0.96		Loss of catalytic residue at I43 (P = 0.2434)
MVP		0.98
MPC		1.5
ClinPred		1.0	D
GERP RS		5.3
PromoterAI		-0.0067	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.90
gMVP		0.85
Mutation Taster		=3/97	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs587776925; hg19: chr1-203832842;