2-230213010-A-G

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.334T>C(p.Trp112Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.891 in 1,613,738 control chromosomes in the GnomAD database, including 641,644 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.92 (64041 hom., cov: 30)
  • Exomes 𝑓: 0.89 (577603 hom.)
• Consequence: SP110 NM_080424.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.189

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=8.1801585E-7).
• BP6: Variant 2-230213010-A-G is Benign according to our data. Variant chr2-230213010-A-G is described in ClinVar as [Benign]. Clinvar id is 403465.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.975 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SP110	NM_080424.4	c.334T>C	p.Trp112Arg	missense_variant	4/19	ENST00000258381.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SP110	ENST00000258381.11	c.334T>C	p.Trp112Arg	missense_variant	4/19	2	NM_080424.4	P1

Frequencies

GnomAD3 genomes AF: 0.917 AC: 139312 AN: 152002 Hom.: 63987 Cov.: 30

Gnomad AFR AF: 0.978

Gnomad AMI AF: 0.879

Gnomad AMR AF: 0.918

Gnomad ASJ AF: 0.924

Gnomad EAS AF: 0.997

Gnomad SAS AF: 0.943

Gnomad FIN AF: 0.867

Gnomad MID AF: 0.927

Gnomad NFE AF: 0.879

Gnomad OTH AF: 0.914

GnomAD3 exomes AF: 0.910 AC: 226551 AN: 248960 Hom.: 103374 AF XY: 0.909 AC XY: 122413 AN XY: 134722

Gnomad AFR exome AF: 0.981

Gnomad AMR exome AF: 0.936

Gnomad ASJ exome AF: 0.925

Gnomad EAS exome AF: 0.998

Gnomad SAS exome AF: 0.938

Gnomad FIN exome AF: 0.868

Gnomad NFE exome AF: 0.877

Gnomad OTH exome AF: 0.897

GnomAD4 exome AF: 0.888 AC: 1298374 AN: 1461618 Hom.: 577603 Cov.: 55 AF XY: 0.890 AC XY: 646874 AN XY: 727134

Gnomad4 AFR exome AF: 0.982

Gnomad4 AMR exome AF: 0.935

Gnomad4 ASJ exome AF: 0.928

Gnomad4 EAS exome AF: 0.999

Gnomad4 SAS exome AF: 0.937

Gnomad4 FIN exome AF: 0.865

Gnomad4 NFE exome AF: 0.875

Gnomad4 OTH exome AF: 0.899

GnomAD4 genome AF: 0.917 AC: 139425 AN: 152120 Hom.: 64041 Cov.: 30 AF XY: 0.917 AC XY: 68175 AN XY: 74336

Gnomad4 AFR AF: 0.978

Gnomad4 AMR AF: 0.919

Gnomad4 ASJ AF: 0.924

Gnomad4 EAS AF: 0.997

Gnomad4 SAS AF: 0.942

Gnomad4 FIN AF: 0.867

Gnomad4 NFE AF: 0.879

Gnomad4 OTH AF: 0.912

Alfa AF: 0.892 Hom.: 106617

Bravo AF: 0.922

TwinsUK AF: 0.872 AC: 3235

ALSPAC AF: 0.879 AC: 3387

ESP6500AA AF: 0.976 AC: 4300

ESP6500EA AF: 0.883 AC: 7598

ExAC AF: 0.909 AC: 110371

Asia WGS AF: 0.962 AC: 3345 AN: 3478

EpiCase AF: 0.885

EpiControl AF: 0.879

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

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 99% of patients studied by a panel of primary immunodeficiencies. Number of patients: 94. 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 -

Hepatic veno-occlusive disease-immunodeficiency syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.53
Cadd	Benign	0.30
Dann	Benign	0.48
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.055	T;T;T;T;T;T;T
MetaRNN	Benign	8.2e-7	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	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	1.4	N;N;N;N;N;N;N
REVEL	Benign	0.28
Sift	Benign	0.36	T;T;T;T;T;T;T
Sift4G	Benign	0.34	T;T;T;T;T;.;T
Polyphen		0.0030	B;B;B;.;.;.;.
Vest4		0.11
MutPred		0.45		Gain of disorder (P = 0.0043);Gain of disorder (P = 0.0043);Gain of disorder (P = 0.0043);Gain of disorder (P = 0.0043);.;Gain of disorder (P = 0.0043);.;
MPC		0.24
ClinPred		0.0023	T
GERP RS		-0.86
Varity_R		0.023
gMVP		0.18

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: rs1129411; hg19: chr2-231077725;