9-15457960-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001039697.2(SNAPC3):c.981G>C(p.Arg327Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000709 in 1,409,598 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: SNAPC3 NM_001039697.2 missense, splice_region
• Scores: Splicing: ADA: 0.9346
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.32

Genes affected

SNAPC3 (HGNC:11136): (small nuclear RNA activating complex polypeptide 3) Predicted to enable RNA polymerase III type 3 promoter sequence-specific DNA binding activity and bent DNA binding activity. Predicted to contribute to RNA polymerase II cis-regulatory region sequence-specific DNA binding activity and core promoter sequence-specific DNA binding activity. Predicted to be involved in snRNA transcription by RNA polymerase II and snRNA transcription by RNA polymerase III. Located in nuclear body and nucleolus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.873

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SNAPC3	NM_001039697.2	c.981G>C	p.Arg327Ser	missense_variant, splice_region_variant	8/9	ENST00000380821.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SNAPC3	ENST00000380821.8	c.981G>C	p.Arg327Ser	missense_variant, splice_region_variant	8/9	1	NM_001039697.2	P1
SNAPC3	ENST00000610884.4	c.981G>C	p.Arg327Ser	missense_variant, splice_region_variant	8/12	1		P1
SNAPC3	ENST00000467062.5	c.981G>C	p.Arg327Ser	missense_variant, splice_region_variant, NMD_transcript_variant	8/12	1
SNAPC3	ENST00000490969.5	c.981G>C	p.Arg327Ser	missense_variant, splice_region_variant, NMD_transcript_variant	8/10	1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000454 AC: 1 AN: 220160 Hom.: 0 AF XY: 0.00000836 AC XY: 1 AN XY: 119602

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000951

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.09e-7 AC: 1 AN: 1409598 Hom.: 0 Cov.: 26 AF XY: 0.00000142 AC XY: 1 AN XY: 702048

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.22e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000487 Hom.: 0

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

Oct 25, 2022

The c.981G>C (p.R327S) alteration is located in exon 8 (coding exon 8) of the SNAPC3 gene. This alteration results from a G to C substitution at nucleotide position 981, causing the arginine (R) at amino acid position 327 to be replaced by a serine (S). 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	0.93
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.17
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.41	T;T
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.93	D
M_CAP	Benign	0.068	D
MetaRNN	Pathogenic	0.87	D;D
MetaSVM	Benign	-0.38	T
MutationAssessor	Pathogenic	3.0	M;M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-5.1	D;.
REVEL	Uncertain	0.47
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.98
MutPred		0.66		Gain of glycosylation at R327 (P = 0.0537);Gain of glycosylation at R327 (P = 0.0537);
MVP		0.87
MPC		0.20
ClinPred		1.0	D
GERP RS		3.3
Varity_R		0.97
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.93
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1403802427; hg19: chr9-15457958;