chr3-141066187-G-A

Position:

• chr3-141066187-G-A

Variant summary

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

The NM_080862.3(SPSB4):​c.83G>A​(p.Gly28Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000725 in 1,380,178 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: SPSB4 NM_080862.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.26

Genes affected

SPSB4 (HGNC:30630): (splA/ryanodine receptor domain and SOCS box containing 4) Enables ubiquitin ligase-substrate adaptor activity. Involved in cellular protein metabolic process; positive regulation of protein polyubiquitination; and regulation of circadian rhythm. Located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

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=0.12749621).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPSB4	NM_080862.3	c.83G>A	p.Gly28Asp	missense_variant	2/3	ENST00000310546.3
SPSB4	XM_017007509.3	c.83G>A	p.Gly28Asp	missense_variant	2/3
SPSB4	XR_924215.4	n.882G>A		non_coding_transcript_exon_variant	2/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPSB4	ENST00000310546.3	c.83G>A	p.Gly28Asp	missense_variant	2/3	1	NM_080862.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.25e-7 AC: 1 AN: 1380178 Hom.: 0 Cov.: 32 AF XY: 0.00000147 AC XY: 1 AN XY: 680840

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000128

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

May 23, 2024

The c.83G>A (p.G28D) alteration is located in exon 3 (coding exon 1) of the SPSB4 gene. This alteration results from a G to A substitution at nucleotide position 83, causing the glycine (G) at amino acid position 28 to be replaced by an aspartic acid (D). 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	Benign	0.12
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Benign	0.086	T
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.43
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.54	T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L
MutationTaster	Benign	0.99	D
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.13
Sift	Benign	0.13	T
Sift4G	Benign	0.20	T
Polyphen		0.0020	B
Vest4		0.19
MutPred		0.26		Loss of MoRF binding (P = 0.0369);
MVP		0.20
MPC		0.70
ClinPred		0.46	T
GERP RS		4.2
Varity_R		0.14
gMVP		0.46

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-140785029;