15-101292039-G-A

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP3 BS2

The NM_003090.4(SNRPA1):​c.232C>T​(p.Arg78Cys) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000826 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000083 (0 hom.)
• Consequence: SNRPA1 NM_003090.4 missense, splice_region
• Scores: Splicing: ADA: 0.9755
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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: Likely_benign. The variant received -3 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• BS2: High AC in GnomAdExome4 at 12 AD gene.

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>T	p.Arg78Cys	missense splice_region	Exon 3 of 9	NP_003081.2	P09661
	SNRPA1	NR_135508.2		n.302C>T		splice_region non_coding_transcript_exon	Exon 3 of 8
	SNRPA1	NR_135506.2		n.152+3058C>T		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>T	p.Arg78Cys	missense splice_region	Exon 3 of 9	ENSP00000254193.6	P09661
	SNRPA1	ENST00000394082.8	TSL:1	n.107+3058C>T		intron	N/A
	SNRPA1	ENST00000540017.6	TSL:1	n.159+3058C>T		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000401 AC: 1 AN: 249412 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000884

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000826 AC: 12 AN: 1452120 Hom.: 0 Cov.: 27 AF XY: 0.00000692 AC XY: 5 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: 0.0000116 AC: 1 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: 0.00000906 AC: 10 AN: 1103628

Other (OTH) AF: 0.0000167 AC: 1 AN: 60046

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	35
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.17	T
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.079	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Uncertain	0.039	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		8.8
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-7.2	D
REVEL	Uncertain	0.55
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.84
MutPred		0.51		Loss of MoRF binding (P = 0.0262)
MVP		0.73
MPC		1.9
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.93
gMVP		0.68
Mutation Taster		=48/52	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.98
dbscSNV1_RF	Pathogenic	0.81
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

Other links and lift over

dbSNP: rs745867854; hg19: chr15-101832244;