rs41309088

chr2-230212968-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_080424.4(SP110):c.376G>A(p.Gly126Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0152 in 1,613,966 control chromosomes in the GnomAD database, including 315 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 0.014 (44 hom., cov: 31)
  • Exomes 𝑓: 0.015 (271 hom.)
• Consequence: SP110 NM_080424.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.240

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=0.0027492046).
• BP6: Variant 2-230212968-C-T is Benign according to our data. Variant chr2-230212968-C-T is described in ClinVar as [Benign]. Clinvar id is 334918.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-230212968-C-T is described in Lovd as [Benign]. Variant chr2-230212968-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0144 (2188/152142) while in subpopulation NFE AF= 0.0171 (1165/67990). AF 95% confidence interval is 0.0163. There are 44 homozygotes in gnomad4. There are 1172 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 44 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SP110	NM_080424.4	c.376G>A	p.Gly126Ser	missense_variant	4/19	ENST00000258381.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SP110	ENST00000258381.11	c.376G>A	p.Gly126Ser	missense_variant	4/19	2	NM_080424.4	P1

Frequencies

GnomAD3 genomes AF: 0.0144 AC: 2188 AN: 152024 Hom.: 44 Cov.: 31

Gnomad AFR AF: 0.00191

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.0115

Gnomad ASJ AF: 0.0196

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00643

Gnomad FIN AF: 0.0589

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0171

Gnomad OTH AF: 0.0135

GnomAD3 exomes AF: 0.0163 AC: 4084 AN: 250082 Hom.: 66 AF XY: 0.0165 AC XY: 2227 AN XY: 135214

Gnomad AFR exome AF: 0.00215

Gnomad AMR exome AF: 0.0104

Gnomad ASJ exome AF: 0.0195

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00582

Gnomad FIN exome AF: 0.0579

Gnomad NFE exome AF: 0.0172

Gnomad OTH exome AF: 0.0209

GnomAD4 exome AF: 0.0153 AC: 22418 AN: 1461824 Hom.: 271 Cov.: 37 AF XY: 0.0152 AC XY: 11046 AN XY: 727218

Gnomad4 AFR exome AF: 0.00170

Gnomad4 AMR exome AF: 0.0103

Gnomad4 ASJ exome AF: 0.0210

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00580

Gnomad4 FIN exome AF: 0.0548

Gnomad4 NFE exome AF: 0.0153

Gnomad4 OTH exome AF: 0.0145

GnomAD4 genome AF: 0.0144 AC: 2188 AN: 152142 Hom.: 44 Cov.: 31 AF XY: 0.0158 AC XY: 1172 AN XY: 74366

Gnomad4 AFR AF: 0.00190

Gnomad4 AMR AF: 0.0114

Gnomad4 ASJ AF: 0.0196

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00664

Gnomad4 FIN AF: 0.0589

Gnomad4 NFE AF: 0.0171

Gnomad4 OTH AF: 0.0128

Alfa AF: 0.0154 Hom.: 29

Bravo AF: 0.00975

TwinsUK AF: 0.0200 AC: 74

ALSPAC AF: 0.0179 AC: 69

ESP6500AA AF: 0.00227 AC: 10

ESP6500EA AF: 0.0170 AC: 146

ExAC AF: 0.0154 AC: 1874

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0175

EpiControl AF: 0.0210

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hepatic veno-occlusive disease-immunodeficiency syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.66
Cadd	Benign	4.9
Dann	Benign	0.65
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.024	N
LIST_S2	Benign	0.66	T;T;T;T;T;T;T
MetaRNN	Benign	0.0027	T;T;T;T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.34	N;N;.;N;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.57	N;N;N;N;N;N;N
REVEL	Benign	0.044
Sift	Benign	0.097	T;T;T;T;T;T;T
Sift4G	Benign	0.37	T;T;T;T;T;.;T
Polyphen		0.037	B;B;B;.;.;.;.
Vest4		0.099
MPC		0.56
ClinPred		0.0071	T
GERP RS		0.90
Varity_R		0.024
gMVP		0.22

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: rs41309088; hg19: chr2-231077683; COSMIC: COSV51248582; COSMIC: COSV51248582;