NM_003094.4:c.1A>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: G2P, PanelApp Australia, Ambry Genetics, 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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SNRPE	NM_003094.4	MANE Select	c.1A>G	p.Met1?	start_lost	Exon 1 of 5	NP_003085.1	P62304
	SNRPE	NM_001304464.2		c.-68A>G		5_prime_UTR	Exon 1 of 5	NP_001291393.1
	SNRPE	NR_130746.2		n.62A>G		non_coding_transcript_exon	Exon 1 of 4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SNRPE	ENST00000414487.7	TSL:1 MANE Select	c.1A>G	p.Met1?	start_lost	Exon 1 of 5	ENSP00000400591.2	P62304
	SNRPE	ENST00000475035.5	TSL:1	n.58A>G		non_coding_transcript_exon	Exon 1 of 5
	SNRPE	ENST00000917033.1		c.1A>G	p.Met1?	start_lost	Exon 1 of 5	ENSP00000587092.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
2	-	-	Hypotrichosis 11 (2)
1	1	-	not provided (2)

Computational scores

Source: dbNSFP v4.9

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;