NM_025106.4:c.776C>A

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_025106.4(SPSB1):​c.776C>A​(p.Thr259Lys) 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. 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)
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06654781).

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>A	p.Thr259Lys	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>A	p.Thr259Lys	missense	Exon 3 of 3	ENSP00000330221.6	Q96BD6
	SPSB1	ENST00000377399.2	TSL:1	c.776C>A	p.Thr259Lys	missense	Exon 2 of 2	ENSP00000366616.2	Q96BD6
	SPSB1	ENST00000357898.3	TSL:5	c.776C>A	p.Thr259Lys	missense	Exon 3 of 3	ENSP00000350573.3	Q96BD6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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	0.092
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	18
DANN	Benign	0.90
DEOGEN2	Benign	0.053	T
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.0060	T
MetaRNN	Benign	0.067	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.36	N
PhyloP100		3.3
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.55	N
REVEL	Benign	0.077
Sift	Benign	0.93	T
Sift4G	Benign	0.94	T
Polyphen		0.0	B
Vest4		0.18
MutPred		0.32		Gain of ubiquitination at T259 (P = 0.0408)
MVP		0.14
MPC		1.1
ClinPred		0.63	D
GERP RS		4.2
Varity_R		0.065
gMVP		0.37
Mutation Taster		=84/16	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;