NM_003090.4:c.232C>G

Variant names:

• chr15-101292039-G-C
• rs745867854
• NM_003090.4:c.232C>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_003090.4(SNRPA1):​c.232C>G​(p.Arg78Gly) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,452,120 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R78C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SNRPA1 NM_003090.4 missense, splice_region
• Scores: Splicing: ADA: 0.9617
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.78
• Publications: 0 publications found

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]

PCSK6 Gene-Disease associations (from GenCC):

• congenital heart disease

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003090.4. 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
	SNRPA1	NM_003090.4	MANE Select	c.232C>G	p.Arg78Gly	missense splice_region	Exon 3 of 9	NP_003081.2	P09661
	SNRPA1	NR_135508.2		n.302C>G		splice_region non_coding_transcript_exon	Exon 3 of 8
	SNRPA1	NR_135506.2		n.152+3058C>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SNRPA1	ENST00000254193.11	TSL:1 MANE Select	c.232C>G	p.Arg78Gly	missense splice_region	Exon 3 of 9	ENSP00000254193.6	P09661
	SNRPA1	ENST00000394082.8	TSL:1	n.107+3058C>G		intron	N/A
	SNRPA1	ENST00000540017.6	TSL:1	n.159+3058C>G		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1452120 Hom.: 0 Cov.: 27 AF XY: 0.00000138 AC XY: 1 AN XY: 723042

African (AFR) AF: 0.00 AC: 0 AN: 33246

American (AMR) AF: 0.00 AC: 0 AN: 44552

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26048

East Asian (EAS) AF: 0.00 AC: 0 AN: 39592

South Asian (SAS) AF: 0.00 AC: 0 AN: 85910

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53356

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5742

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1103628

Other (OTH) AF: 0.00 AC: 0 AN: 60046

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.061	D
MetaRNN	Pathogenic	0.80	D
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Benign	1.3	L
PhyloP100		8.8
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-6.2	D
REVEL	Uncertain	0.57
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.84
MutPred		0.50		Loss of MoRF binding (P = 0.0311)
MVP		0.80
MPC		1.9
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.97
gMVP		0.77
Mutation Taster		=36/64	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.96
dbscSNV1_RF	Pathogenic	0.78
SpliceAI score (max)		0.070		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: rs745867854; hg19: chr15-101832244;