rs199845488

Variant names:

• chr2-230208012-T-A
• rs199845488
• NM_080424.4:c.877A>T

Your query was ambiguous. Multiple possible variants found:

• chr2-230208012-T-A
• chr2-230208012-T-C

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_080424.4(SP110):​c.877A>T​(p.Lys293*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000707 in 1,413,614 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: SP110 NM_080424.4 stop_gained
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.0410
• Publications: 0 publications found

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

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-230208012-T-A is Pathogenic according to our data. Variant chr2-230208012-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 189244.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SP110	NM_080424.4	c.877A>T	p.Lys293*	stop_gained	Exon 8 of 19	ENST00000258381.11	NP_536349.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SP110	ENST00000258381.11	c.877A>T	p.Lys293*	stop_gained	Exon 8 of 19	2	NM_080424.4	ENSP00000258381.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.07e-7 AC: 1 AN: 1413614 Hom.: 0 Cov.: 25 AF XY: 0.00000142 AC XY: 1 AN XY: 705608

African (AFR) AF: 0.00 AC: 0 AN: 32286

American (AMR) AF: 0.00 AC: 0 AN: 44192

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25594

East Asian (EAS) AF: 0.00 AC: 0 AN: 39442

South Asian (SAS) AF: 0.00 AC: 0 AN: 84380

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52906

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5658

European-Non Finnish (NFE) AF: 9.34e-7 AC: 1 AN: 1070668

Other (OTH) AF: 0.00 AC: 0 AN: 58488

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hepatic veno-occlusive disease-immunodeficiency syndrome Pathogenic:1

Jan 27, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.877A>T_p.Lys293X variant in SP110 has not been reported in individuals with veno-occlusive disease with immunodeficiency or in large population studies. This nonsense variant leads to a premature termination codon at position 293, which is predicted to lead to a truncated or absent protein. Several other truncating variants have been reported and they are associated with autosomal recessive hepatic veno-occlusive disease with immunodeficiency (Roscioli 2006; Cliffe 2012). In summary, this variant is likely pathogenic, though additional studies are required to fully establish its clinical significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Uncertain	0.020
CADD	Pathogenic	32
DANN	Benign	0.96
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.016	N
PhyloP100		0.041
Vest4		0.88
GERP RS		-0.94
Mutation Taster		=47/153	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs199845488; hg19: chr2-231072727;