16-1777748-T-C

Position:

• chr16-1777748-T-C

Variant summary

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

The NM_080861.4(SPSB3):​c.720A>G​(p.Ile240Met) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,459,984 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: SPSB3 NM_080861.4 missense, splice_region
• Scores: Splicing: ADA: 0.6264
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.83

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPSB3	NM_080861.4	c.720A>G	p.Ile240Met	missense_variant, splice_region_variant	6/7	ENST00000566339.6
EME2	NM_001257370.2	c.*1510T>C		3_prime_UTR_variant	8/8	ENST00000568449.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPSB3	ENST00000566339.6	c.720A>G	p.Ile240Met	missense_variant, splice_region_variant	6/7	1	NM_080861.4	P1
EME2	ENST00000568449.7	c.*1510T>C		3_prime_UTR_variant	8/8	1	NM_001257370.2	P1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD3 exomes AF: 0.0000360 AC: 9 AN: 249988 Hom.: 0 AF XY: 0.0000295 AC XY: 4 AN XY: 135600

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000490

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1459984 Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3 AN XY: 726306

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 34

ExAC AF: 0.0000412 AC: 5

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.11
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.067	T;T
Eigen	Benign	0.081
Eigen_PC	Benign	0.051
FATHMM_MKL	Uncertain	0.91	D
M_CAP	Uncertain	0.10	D
MetaRNN	Uncertain	0.58	D;D
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	0.58	N;N
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.55	N;N
Sift	Uncertain	0.022	D;D
Sift4G	Uncertain	0.029	D;D
Polyphen		0.97	D;D
Vest4		0.79
MutPred		0.66		Loss of sheet (P = 0.0357);Loss of sheet (P = 0.0357);
MVP		0.76
MPC		0.91
ClinPred		0.16	T
GERP RS		2.6
Varity_R		0.23
gMVP		0.62

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.63
dbscSNV1_RF	Benign	0.70
SpliceAI score (max)		0.27		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.27		Position offset: 5

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

Publications

LitVar

Other links and lift over

dbSNP: rs774420958; hg19: chr16-1827749;