dbSNP rs373548222: SPSB1:p.Arg225Ser (chr1-9356564-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_025106.4(SPSB1):c.673C>A(p.Arg225Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000691 in 1,446,496 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R225C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

SPSB1
NM_025106.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.87

Publications

0 publications found

Variant links:

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]

SPSB1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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.673C>A	p.Arg225Ser	missense	Exon 2 of 3	NP_079382.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SPSB1	ENST00000328089.11	TSL:1 MANE Select	c.673C>A	p.Arg225Ser	missense	Exon 2 of 3	ENSP00000330221.6	Q96BD6
SPSB1	ENST00000377399.2	TSL:1	c.673C>A	p.Arg225Ser	missense	Exon 1 of 2	ENSP00000366616.2	Q96BD6
SPSB1	ENST00000357898.3	TSL:5	c.673C>A	p.Arg225Ser	missense	Exon 2 of 3	ENSP00000350573.3	Q96BD6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.91e-7

AC:

AN:

1446496

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

716522

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33170

American (AMR)

AF:

0.0000226

AC:

AN:

44270

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25652

East Asian (EAS)

AF:

0.00

AC:

AN:

39338

South Asian (SAS)

AF:

0.00

AC:

AN:

85280

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52796

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5720

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1100586

Other (OTH)

AF:

0.00

AC:

AN:

59684

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.44

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Uncertain

-0.080

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.31

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.92

M_CAP

Benign

0.023

MetaRNN

Uncertain

0.63

MetaSVM

Benign

-0.82

MutationAssessor

Uncertain

2.7

PhyloP100

4.9

PrimateAI

Uncertain

0.73

PROVEAN

Uncertain

-3.2

REVEL

Benign

0.26

Sift

Benign

0.20

Sift4G

Benign

0.23

Polyphen

0.95

Vest4

0.60

MutPred

0.63

Gain of sheet (P = 0.0344)

MVP

0.45

MPC

1.2

ClinPred

0.97

GERP RS

4.2

Varity_R

0.75

gMVP

0.89

Mutation Taster

=22/78

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over