rs28930679

Positions:

• chr2-230212397-G-A
• chr2-230212397-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_080424.4(SP110):​c.617C>T​(p.Ala206Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.231 in 1,606,272 control chromosomes in the GnomAD database, including 44,658 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A206E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.21 (3464 hom., cov: 32)
  • Exomes 𝑓: 0.23 (41194 hom.)
• Consequence: SP110 NM_080424.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.0930

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]

SP140 (HGNC:17133): (SP140 nuclear body protein) This gene encodes a member of the SP100 family of proteins, which are share common domains including an N-terminal homogeneously staining region domain followed by a SP100/autoimmune regulator/NucP41/P75/deformed epidermal autoregulatory factor domain, a plant homeobox zinc finger, and a bromodomain. The encoded protein is interferon-inducible and is expressed at high levels in the nuclei of leukocytes. Variants of this gene have been associated with multiple sclerosis, Crohn's disease, and chronic lymphocytic leukemia. Alternative splicing results in multiple variants. [provided by RefSeq, Aug 2016]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010025024).
• BP6: Variant 2-230212397-G-A is Benign according to our data. Variant chr2-230212397-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 334911.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-230212397-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.242 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SP110	NM_080424.4	c.617C>T	p.Ala206Val	missense_variant	5/19	ENST00000258381.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SP110	ENST00000258381.11	c.617C>T	p.Ala206Val	missense_variant	5/19	2	NM_080424.4	P1

Frequencies

GnomAD3 genomes AF: 0.205 AC: 31231 AN: 151984 Hom.: 3464 Cov.: 32

Gnomad AFR AF: 0.142

Gnomad AMI AF: 0.257

Gnomad AMR AF: 0.220

Gnomad ASJ AF: 0.286

Gnomad EAS AF: 0.0972

Gnomad SAS AF: 0.166

Gnomad FIN AF: 0.211

Gnomad MID AF: 0.282

Gnomad NFE AF: 0.245

Gnomad OTH AF: 0.237

GnomAD3 exomes AF: 0.214 AC: 53736 AN: 250976 Hom.: 6019 AF XY: 0.215 AC XY: 29204 AN XY: 135626

Gnomad AFR exome AF: 0.144

Gnomad AMR exome AF: 0.244

Gnomad ASJ exome AF: 0.282

Gnomad EAS exome AF: 0.0847

Gnomad SAS exome AF: 0.176

Gnomad FIN exome AF: 0.203

Gnomad NFE exome AF: 0.241

Gnomad OTH exome AF: 0.238

GnomAD4 exome AF: 0.234 AC: 340263 AN: 1454170 Hom.: 41194 Cov.: 32 AF XY: 0.233 AC XY: 168649 AN XY: 723754

Gnomad4 AFR exome AF: 0.144

Gnomad4 AMR exome AF: 0.243

Gnomad4 ASJ exome AF: 0.286

Gnomad4 EAS exome AF: 0.107

Gnomad4 SAS exome AF: 0.180

Gnomad4 FIN exome AF: 0.207

Gnomad4 NFE exome AF: 0.245

Gnomad4 OTH exome AF: 0.231

GnomAD4 genome AF: 0.205 AC: 31238 AN: 152102 Hom.: 3464 Cov.: 32 AF XY: 0.203 AC XY: 15126 AN XY: 74372

Gnomad4 AFR AF: 0.142

Gnomad4 AMR AF: 0.220

Gnomad4 ASJ AF: 0.286

Gnomad4 EAS AF: 0.0967

Gnomad4 SAS AF: 0.166

Gnomad4 FIN AF: 0.211

Gnomad4 NFE AF: 0.245

Gnomad4 OTH AF: 0.233

Alfa AF: 0.234 Hom.: 6038

Bravo AF: 0.206

TwinsUK AF: 0.243 AC: 901

ALSPAC AF: 0.257 AC: 992

ESP6500AA AF: 0.141 AC: 623

ESP6500EA AF: 0.253 AC: 2177

ExAC AF: 0.211 AC: 25613

Asia WGS AF: 0.107 AC: 375 AN: 3478

EpiCase AF: 0.259

EpiControl AF: 0.258

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hepatic veno-occlusive disease-immunodeficiency syndrome Benign:4

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 03, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jan 24, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 52% of patients studied by a panel of primary immunodeficiencies. Number of patients: 49. Only high quality variants are reported. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 23, 2019

This variant is associated with the following publications: (PMID: 30697212) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	7.7
DANN	Benign	0.89
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.63	T;T;T;T;T;T;T
MetaRNN	Benign	0.0046	T;T;T;T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.0	N;N;.;N;.;.;.
MutationTaster	Benign	1.0	P;P;P;P;P;P
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.43	N;N;N;N;N;N;N
REVEL	Benign	0.043
Sift	Benign	0.050	D;D;T;T;T;D;D
Sift4G	Benign	0.28	T;T;T;T;T;.;D
Polyphen		0.0010	B;B;B;.;.;.;.
Vest4		0.051
MPC		0.13
ClinPred		0.00012	T
GERP RS		-0.15
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.022
gMVP		0.11

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: rs28930679; hg19: chr2-231077112; COSMIC: COSV51249759; COSMIC: COSV51249759;