9-113349640-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_017688.3(BSPRY):c.61C>T(p.Leu21Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000933 in 1,072,378 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 9.3e-7 (0 hom.)
• Consequence: BSPRY NM_017688.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.225

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.40591764).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BSPRY	NM_017688.3	c.61C>T	p.Leu21Phe	missense_variant	1/6	ENST00000374183.5
BSPRY	NM_001317943.2	c.61C>T	p.Leu21Phe	missense_variant	1/6
BSPRY	NM_001317944.2	c.61C>T	p.Leu21Phe	missense_variant	1/5
BSPRY	XM_006717149.4	c.61C>T	p.Leu21Phe	missense_variant	1/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BSPRY	ENST00000374183.5	c.61C>T	p.Leu21Phe	missense_variant	1/6	1	NM_017688.3	P1
BSPRY	ENST00000462085.1	n.99C>T		non_coding_transcript_exon_variant	1/5	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 9.33e-7 AC: 1 AN: 1072378 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 511128

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: 0.00000109

Gnomad4 OTH exome AF: 0.00

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

Jul 20, 2021

The c.61C>T (p.L21F) alteration is located in exon 1 (coding exon 1) of the BSPRY gene. This alteration results from a C to T substitution at nucleotide position 61, causing the leucine (L) at amino acid position 21 to be replaced by a phenylalanine (F). 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	-0.20	T
BayesDel_noAF	Benign	-0.52
Cadd	Benign	17
Dann	Uncertain	0.99
DEOGEN2	Benign	0.018	T
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.014	N
LIST_S2	Benign	0.47	T
M_CAP	Pathogenic	0.43	D
MetaRNN	Benign	0.41	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M
MutationTaster	Benign	1.0	N
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.11
Sift	Benign	0.11	T
Sift4G	Uncertain	0.051	T
Polyphen		0.86	P
Vest4		0.13
MutPred		0.41		Loss of catalytic residue at L21 (P = 0.1847);
MVP		0.52
MPC		0.28
ClinPred		0.41	T
GERP RS		2.1
Varity_R		0.11
gMVP		0.17

Splicing

Name	Calibrated prediction	Score	Prediction
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: chr9-116111920;