16-1777415-C-G

Position:

• chr16-1777415-C-G

Variant summary

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

The NM_080861.4(SPSB3):​c.750G>C​(p.Lys250Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 34)
• Consequence: SPSB3 NM_080861.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.44

Genes affected

SPSB3 (HGNC:30629): (splA/ryanodine receptor domain and SOCS box containing 3) Predicted to be involved in proteasome-mediated ubiquitin-dependent protein catabolic process. Predicted to be located in cytosol. Predicted to be part of SCF ubiquitin ligase complex. [provided by Alliance of Genome Resources, Apr 2022]

EME2 (HGNC:27289): (essential meiotic structure-specific endonuclease subunit 2) EME2 forms a heterodimer with MUS81 (MIM 606591) that functions as an XPF (MIM 278760)-type flap/fork endonuclease in DNA repair (Ciccia et al., 2007 [PubMed 17289582]).[supplied by OMIM, Mar 2008]

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=0.25688338).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPSB3	NM_080861.4	c.750G>C	p.Lys250Asn	missense_variant	7/7	ENST00000566339.6
EME2	NM_001257370.2	c.*1177C>G		3_prime_UTR_variant	8/8	ENST00000568449.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPSB3	ENST00000566339.6	c.750G>C	p.Lys250Asn	missense_variant	7/7	1	NM_080861.4	P1
EME2	ENST00000568449.7	c.*1177C>G		3_prime_UTR_variant	8/8	1	NM_001257370.2	P1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 34

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

Feb 06, 2024

The c.750G>C (p.K250N) alteration is located in exon 7 (coding exon 6) of the SPSB3 gene. This alteration results from a G to C substitution at nucleotide position 750, causing the lysine (K) at amino acid position 250 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	Pathogenic	0.59
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T;T
Eigen	Uncertain	0.24
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.88	.;D
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.26	T;T
MetaSVM	Benign	-0.55	T
MutationAssessor	Uncertain	2.2	M;M
MutationTaster	Benign	0.98	D;D
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.7	N;N
REVEL	Benign	0.16
Sift	Benign	0.14	T;T
Sift4G	Uncertain	0.036	D;D
Polyphen		0.98	D;D
Vest4		0.31
MutPred		0.39		Loss of methylation at K250 (P = 0.0111);Loss of methylation at K250 (P = 0.0111);
MVP		0.41
MPC		1.1
ClinPred		0.90	D
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.15
gMVP		0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr16-1827416;