1-203861660-A-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PS1_Moderate PM2

The NM_003094.4(SNRPE):c.1A>T(p.Met1?) variant causes a start lost change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SNRPE NM_003094.4 start_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.80

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_003094.4 (SNRPE) was described as [Likely_pathogenic] in ClinVar as 39505
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SNRPE	NM_003094.4	c.1A>T	p.Met1?	start_lost	1/5	ENST00000414487.7
SNRPE	NM_001304464.2	c.-68A>T		5_prime_UTR_variant	1/5
SNRPE	NR_130746.2	n.62A>T		non_coding_transcript_exon_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SNRPE	ENST00000414487.7	c.1A>T	p.Met1?	start_lost	1/5	1	NM_003094.4	P1
SNRPE	ENST00000475035.5	n.58A>T		non_coding_transcript_exon_variant	1/5	1
SNRPE	ENST00000470492.5	n.52A>T		non_coding_transcript_exon_variant	1/4	3
SNRPE	ENST00000483099.5	n.58A>T		non_coding_transcript_exon_variant	1/4	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 03, 2021

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Disruption of the initiator codon has been observed in individual(s) with hypotrichosis simplex (PMID: 23246290). This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the SNRPE mRNA. The next in-frame methionine is located at codon 14. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
Cadd	Uncertain	24
Dann	Uncertain	0.97
DEOGEN2	Benign	0.20	T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Benign	0.71	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.56	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Benign	-0.29	T
MutationTaster	Benign	1.0	D
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.44
Sift	Uncertain	0.011	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.70	P
Vest4		0.95
MutPred		0.66		Gain of stability (P = 0.0258);
MVP		0.88
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.85
gMVP		0.71

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-203830788;