9-113360508-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_017688.3(BSPRY):c.302G>A(p.Ser101Asn) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000139 in 1,438,458 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 18/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: BSPRY NM_017688.3 missense, splice_region
• Scores: Splicing: ADA: 0.0001687
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.856

Genes affected

BSPRY (HGNC:18232): (B-box and SPRY domain containing) Predicted to enable ubiquitin protein ligase activity. Predicted to be involved in protein ubiquitination. Predicted to act upstream of or within cellular response to leukemia inhibitory factor. Predicted to be located in cell leading edge; membrane; and perinuclear region of cytoplasm. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.075525135).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BSPRY	NM_017688.3	c.302G>A	p.Ser101Asn	missense_variant, splice_region_variant	3/6	ENST00000374183.5
BSPRY	NM_001317943.2	c.302G>A	p.Ser101Asn	missense_variant, splice_region_variant	3/6
BSPRY	NM_001317944.2	c.302G>A	p.Ser101Asn	missense_variant, splice_region_variant	3/5
BSPRY	XM_006717149.4	c.302G>A	p.Ser101Asn	missense_variant, splice_region_variant	3/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BSPRY	ENST00000374183.5	c.302G>A	p.Ser101Asn	missense_variant, splice_region_variant	3/6	1	NM_017688.3	P1
BSPRY	ENST00000462085.1	n.340G>A		splice_region_variant, non_coding_transcript_exon_variant	3/5	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000139 AC: 2 AN: 1438458 Hom.: 0 Cov.: 31 AF XY: 0.00000140 AC XY: 1 AN XY: 712930

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: 0.00

Gnomad4 OTH exome AF: 0.0000168

GnomAD4 genome Cov.: 32

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

Sep 12, 2023

The c.302G>A (p.S101N) alteration is located in exon 3 (coding exon 3) of the BSPRY gene. This alteration results from a G to A substitution at nucleotide position 302, causing the serine (S) at amino acid position 101 to be replaced by an asparagine (N). 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	Benign	0.12
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.63
Cadd	Benign	16
Dann	Benign	0.73
DEOGEN2	Benign	0.0056	T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.45
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.53	T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.076	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L
MutationTaster	Benign	0.98	N
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.77	N
REVEL	Benign	0.046
Sift	Benign	0.36	T
Sift4G	Benign	0.14	T
Polyphen		0.0060	B
Vest4		0.095
MutPred		0.26		Loss of phosphorylation at S101 (P = 0.0444);
MVP		0.43
MPC		0.065
ClinPred		0.27	T
GERP RS		2.6
Varity_R		0.066
gMVP		0.084

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00017
dbscSNV1_RF	Benign	0.050
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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-116122788;