1-203861660-A-G

Variant names:

• chr1-203861660-A-G
• rs587776924
• NM_003094.4:c.1A>G

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PVS1_Moderate PM2 PP5

The NM_003094.4(SNRPE):​c.1A>G​(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 Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SNRPE NM_003094.4 start_lost
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 6.80
• Publications: 1 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

ENSG00000297888 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 1 pathogenic variants. Next in-frame start position is after 14 codons. Genomic position: 203861699. Lost 0.143 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-203861660-A-G is Pathogenic according to our data. Variant chr1-203861660-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 39505.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SNRPE	NM_003094.4	c.1A>G	p.Met1?	start_lost	Exon 1 of 5	ENST00000414487.7	NP_003085.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SNRPE	ENST00000414487.7	c.1A>G	p.Met1?	start_lost	Exon 1 of 5	1	NM_003094.4	ENSP00000400591.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hypotrichosis 11 Pathogenic:2

-

3billion

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Start-lost: reinitiation of translation may occur at a downstream alternate start codon but still result in a loss or disruption of normal protein function (PMID:. 23246290). The variant has been reported to co-segregate with the disease in at least 5 similarly affected relatives/individuals in the same family or similarly affected unrelated families (PMID: 23246290). The variant has been reported to be associated with SNRPE related disorder (ClinVar ID: VCV000039505 / PMID: 23246290). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -

Jan 10, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1 Uncertain:1

Sep 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects the initiator methionine of the SNRPE mRNA. The next in-frame methionine is located at codon 14. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individual(s) with hypotrichosis simplex (PMID: 23246290, 33792916). ClinVar contains an entry for this variant (Variation ID: 39505). 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. -

Jun 28, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); Initiation codon variant in a gene for which loss of function is not a known mechanism of disease; This variant is associated with the following publications: (PMID: 23246290, 33792916) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Benign	0.70	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.68	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Uncertain	-0.18	T
PhyloP100		6.8
PROVEAN	Benign	-1.8	N
REVEL	Pathogenic	0.72
Sift	Benign	0.052	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.92	P
Vest4		0.97
MutPred		0.65		Gain of loop (P = 0.1081);
MVP		0.87
ClinPred		1.0	D
GERP RS		5.6
PromoterAI		-0.40	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.72
gMVP		0.81
Mutation Taster		=35/165	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: rs587776924; hg19: chr1-203830788;