chr15-101293128-G-C

Position:

• chr15-101293128-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_003090.4(SNRPA1):​c.127C>G​(p.Gln43Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SNRPA1 NM_003090.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.34

Genes affected

SNRPA1 (HGNC:11152): (small nuclear ribonucleoprotein polypeptide A') Enables RNA binding activity. Involved in mRNA splicing, via spliceosome and spermatogenesis. Located in nuclear speck. Part of U2-type catalytic step 2 spliceosome and U2-type precatalytic spliceosome. Implicated in connective tissue disease. [provided by Alliance of Genome Resources, Apr 2022]

PCSK6 (HGNC:8569): (proprotein convertase subtilisin/kexin type 6) This gene encodes a member of the subtilisin-like proprotein convertase family, which includes proteases that process protein and peptide precursors trafficking through regulated or constitutive branches of the secretory pathway. The encoded protein undergoes an initial autocatalytic processing event in the ER to generate a heterodimer which exits the ER and sorts to the trans-Golgi network where a second autocatalytic event takes place and the catalytic activity is acquired. The encoded protease is constitutively secreted into the extracellular matrix and expressed in many tissues, including neuroendocrine, liver, gut, and brain. This gene encodes one of the seven basic amino acid-specific members which cleave their substrates at single or paired basic residues. Some of its substrates include transforming growth factor beta related proteins, proalbumin, and von Willebrand factor. This gene is thought to play a role in tumor progression and left-right patterning. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Feb 2014]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SNRPA1	NM_003090.4	c.127C>G	p.Gln43Glu	missense_variant	2/9	ENST00000254193.11	NP_003081.2
SNRPA1	NR_135508.2	n.197C>G		non_coding_transcript_exon_variant	2/8
SNRPA1	NR_135506.2	n.152+1969C>G		intron_variant
SNRPA1	NR_135507.2	n.152+1969C>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SNRPA1	ENST00000254193.11	c.127C>G	p.Gln43Glu	missense_variant	2/9	1	NM_003090.4	ENSP00000254193.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 19, 2024

The c.127C>G (p.Q43E) alteration is located in exon 2 (coding exon 2) of the SNRPA1 gene. This alteration results from a C to G substitution at nucleotide position 127, causing the glutamine (Q) at amino acid position 43 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Uncertain	0.073	D
BayesDel_noAF	Benign	-0.13
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T;.
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Benign	0.022	T
MetaRNN	Uncertain	0.61	D;D
MetaSVM	Benign	-0.47	T
MutationAssessor	Benign	1.8	L;.
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-2.8	D;.
REVEL	Uncertain	0.33
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.68
MutPred		0.38		Loss of sheet (P = 0.1398);Loss of sheet (P = 0.1398);
MVP		0.62
MPC		1.7
ClinPred		0.99	D
GERP RS		4.9
Varity_R		0.94
gMVP		0.66

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-101833333;