1-9367529-C-G

Variant names:

• chr1-9367529-C-G
• rs770144020
• NM_025106.4:c.776C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_025106.4(SPSB1):​c.776C>G​(p.Thr259Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,564 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T259M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SPSB1 NM_025106.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.31
• Publications: 1 publications found

Genes affected

SPSB1 (HGNC:30628): (splA/ryanodine receptor domain and SOCS box containing 1) Enables ubiquitin ligase-substrate adaptor activity. Involved in protein ubiquitination and ubiquitin-dependent protein catabolic process. Located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08455491).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_025106.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPSB1	NM_025106.4	MANE Select	c.776C>G	p.Thr259Arg	missense	Exon 3 of 3	NP_079382.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPSB1	ENST00000328089.11	TSL:1 MANE Select	c.776C>G	p.Thr259Arg	missense	Exon 3 of 3	ENSP00000330221.6	Q96BD6
	SPSB1	ENST00000377399.2	TSL:1	c.776C>G	p.Thr259Arg	missense	Exon 2 of 2	ENSP00000366616.2	Q96BD6
	SPSB1	ENST00000357898.3	TSL:5	c.776C>G	p.Thr259Arg	missense	Exon 3 of 3	ENSP00000350573.3	Q96BD6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460564 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726570

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44674

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26090

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.00 AC: 0 AN: 86218

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52924

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5702

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111500

Other (OTH) AF: 0.00 AC: 0 AN: 60310

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	18
DANN	Benign	0.96
DEOGEN2	Benign	0.054	T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.0051	T
MetaRNN	Benign	0.085	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		3.3
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.14	N
REVEL	Benign	0.049
Sift	Benign	0.43	T
Sift4G	Benign	0.46	T
Polyphen		0.0	B
Vest4		0.17
MutPred		0.31		Gain of MoRF binding (P = 0.0472)
MVP		0.15
MPC		1.1
ClinPred		0.18	T
GERP RS		4.2
Varity_R		0.062
gMVP		0.39
Mutation Taster		=86/14	polymorphism

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

Other links and lift over

dbSNP: rs770144020; hg19: chr1-9427588;