2-230169144-C-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_080424.4(SP110):c.2122G>C(p.Gly708Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000892 in 1,612,512 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G708S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00049 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00093 (3 hom.)
• Consequence: SP110 NM_080424.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.471

Genes affected

SP110 (HGNC:5401): (SP110 nuclear body protein) The nuclear body is a multiprotein complex that may have a role in the regulation of gene transcription. This gene is a member of the SP100/SP140 family of nuclear body proteins and encodes a leukocyte-specific nuclear body component. The protein can function as an activator of gene transcription and may serve as a nuclear hormone receptor coactivator. In addition, it has been suggested that the protein may play a role in ribosome biogenesis and in the induction of myeloid cell differentiation. Alternative splicing has been observed for this gene and three transcript variants, encoding distinct isoforms, have been identified. [provided by RefSeq, Jul 2008]

(HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013007194).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000493 (75/152074) while in subpopulation NFE AF= 0.000839 (57/67976). AF 95% confidence interval is 0.000664. There are 0 homozygotes in gnomad4. There are 30 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SP110	NM_080424.4	c.2122G>C	p.Gly708Arg	missense_variant	19/19	ENST00000258381.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SP110	ENST00000258381.11	c.2122G>C	p.Gly708Arg	missense_variant	19/19	2	NM_080424.4	P1
	ENST00000628587.2	n.1003+1492C>G		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.000494 AC: 75 AN: 151956 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000218

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000525

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000838

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000378 AC: 95 AN: 251420 Hom.: 0 AF XY: 0.000390 AC XY: 53 AN XY: 135874

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000723

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000554

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000933 AC: 1363 AN: 1460438 Hom.: 3 Cov.: 29 AF XY: 0.000877 AC XY: 637 AN XY: 726616

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.000693

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00117

Gnomad4 OTH exome AF: 0.000497

GnomAD4 genome AF: 0.000493 AC: 75 AN: 152074 Hom.: 0 Cov.: 31 AF XY: 0.000404 AC XY: 30 AN XY: 74344

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.000524

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000839

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000721 Hom.: 0

Bravo AF: 0.000487

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000778 AC: 3

ExAC AF: 0.000264 AC: 32

EpiCase AF: 0.000491

EpiControl AF: 0.000474

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hepatic veno-occlusive disease-immunodeficiency syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 17, 2022	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 684 of the SP110 protein (p.Gly684Arg). This variant is present in population databases (rs181058279, gnomAD 0.07%). This variant has not been reported in the literature in individuals affected with SP110-related conditions. ClinVar contains an entry for this variant (Variation ID: 577709). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.79
Cadd	Benign	1.3
Dann	Benign	0.75
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.47	T;T
M_CAP	Benign	0.0044	T
MetaRNN	Benign	0.013	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.45	N;N
REVEL	Benign	0.045
Sift	Benign	0.082	T;T
Sift4G	Benign	0.094	T;D
Polyphen		0.013	B;B
Vest4		0.16
MVP		0.23
MPC		0.65
ClinPred		0.027	T
GERP RS		-5.2
Varity_R		0.047
gMVP		0.17

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

LitVar

Other links and lift over

dbSNP: rs181058279; hg19: chr2-231033860;