rs59573011

Variant names:

• chr2-230200914-G-A
• rs59573011
• NM_080424.4:c.1100C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_080424.4(SP110):​c.1100C>T​(p.Thr367Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00276 in 1,613,672 control chromosomes in the GnomAD database, including 105 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T367T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.015 (59 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (46 hom.)
• Consequence: SP110 NM_080424.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.0530
• Publications: 5 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0025132895).
• BP6: Variant 2-230200914-G-A is Benign according to our data. Variant chr2-230200914-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 235324.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0502 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_080424.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SP110	NM_080424.4	MANE Select	c.1100C>T	p.Thr367Met	missense	Exon 10 of 19	NP_536349.3	Q9HB58-6
	SP110	NM_001378442.1		c.1118C>T	p.Thr373Met	missense	Exon 11 of 20	NP_001365371.1
	SP110	NM_001378443.1		c.1100C>T	p.Thr367Met	missense	Exon 10 of 19	NP_001365372.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SP110	ENST00000258381.11	TSL:2 MANE Select	c.1100C>T	p.Thr367Met	missense	Exon 10 of 19	ENSP00000258381.6	Q9HB58-6
	SP110	ENST00000358662.9	TSL:1	c.1100C>T	p.Thr367Met	missense	Exon 10 of 18	ENSP00000351488.4	Q9HB58-1
	SP110	ENST00000258382.10	TSL:1	c.1100C>T	p.Thr367Met	missense	Exon 10 of 15	ENSP00000258382.5	Q9HB58-3

Frequencies

GnomAD3 genomes AF: 0.0150 AC: 2283 AN: 152070 Hom.: 59 Cov.: 32

Gnomad AFR AF: 0.0517

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00766

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00669

GnomAD2 exomes AF: 0.00388 AC: 975 AN: 251420 AF XY: 0.00264

Gnomad AFR exome AF: 0.0532

Gnomad AMR exome AF: 0.00228

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000114

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.00148 AC: 2169 AN: 1461484 Hom.: 46 Cov.: 30 AF XY: 0.00125 AC XY: 906 AN XY: 727094

African (AFR) AF: 0.0522 AC: 1746 AN: 33454

American (AMR) AF: 0.00262 AC: 117 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39694

South Asian (SAS) AF: 0.0000812 AC: 7 AN: 86250

European-Finnish (FIN) AF: 0.0000562 AC: 3 AN: 53420

Middle Eastern (MID) AF: 0.000521 AC: 3 AN: 5762

European-Non Finnish (NFE) AF: 0.0000747 AC: 83 AN: 1111676

Other (OTH) AF: 0.00346 AC: 209 AN: 60370

GnomAD4 genome AF: 0.0150 AC: 2286 AN: 152188 Hom.: 59 Cov.: 32 AF XY: 0.0146 AC XY: 1085 AN XY: 74396

African (AFR) AF: 0.0516 AC: 2142 AN: 41502

American (AMR) AF: 0.00765 AC: 117 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4816

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10602

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68006

Other (OTH) AF: 0.00662 AC: 14 AN: 2114

Alfa AF: 0.00562 Hom.: 43

Bravo AF: 0.0175

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0524 AC: 231

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00468 AC: 568

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Hepatic veno-occlusive disease-immunodeficiency syndrome (2)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	16
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0026	T
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.014	N
LIST_S2	Benign	0.67	T
MetaRNN	Benign	0.0025	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	N
PhyloP100		-0.053
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.64	N
REVEL	Benign	0.052
Sift	Benign	0.19	T
Sift4G	Benign	0.12	T
Polyphen		0.51	P
Vest4		0.20
MVP		0.69
MPC		0.55
ClinPred		0.014	T
GERP RS		-0.63
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.029
gMVP		0.078
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs59573011; hg19: chr2-231065630; COSMIC: COSV99033216; COSMIC: COSV99033216;