rs3948463

Variant names:

• chr2-230172144-C-T
• rs3948463
• NM_080424.4:c.1737G>A

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.1737G>A​(p.Met579Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0674 in 1,611,874 control chromosomes in the GnomAD database, including 4,258 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.053 (301 hom., cov: 33)
  • Exomes 𝑓: 0.069 (3957 hom.)
• Consequence: SP110 NM_080424.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.229
• Publications: 18 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]

SP110 Gene-Disease associations (from GenCC):

• hepatic veno-occlusive disease-immunodeficiency syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Orphanet, ClinGen, Ambry Genetics

ENSG00000225963 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0022109747).
• BP6: Variant 2-230172144-C-T is Benign according to our data. Variant chr2-230172144-C-T is described in ClinVar as Benign. ClinVar VariationId is 334897.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.078 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.1737G>A	p.Met579Ile	missense	Exon 16 of 19	NP_536349.3	Q9HB58-6
	SP110	NM_001378442.1		c.1755G>A	p.Met585Ile	missense	Exon 17 of 20	NP_001365371.1
	SP110	NM_001378443.1		c.1737G>A	p.Met579Ile	missense	Exon 16 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.1737G>A	p.Met579Ile	missense	Exon 16 of 19	ENSP00000258381.6	Q9HB58-6
	SP110	ENST00000358662.9	TSL:1	c.1737G>A	p.Met579Ile	missense	Exon 16 of 18	ENSP00000351488.4	Q9HB58-1
	SP110	ENST00000897327.1		c.1737G>A	p.Met579Ile	missense	Exon 17 of 19	ENSP00000567386.1

Frequencies

GnomAD3 genomes AF: 0.0531 AC: 8089 AN: 152208 Hom.: 301 Cov.: 33

Gnomad AFR AF: 0.0131

Gnomad AMI AF: 0.0669

Gnomad AMR AF: 0.0521

Gnomad ASJ AF: 0.136

Gnomad EAS AF: 0.00231

Gnomad SAS AF: 0.0538

Gnomad FIN AF: 0.0339

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.0797

Gnomad OTH AF: 0.0632

GnomAD2 exomes AF: 0.0599 AC: 15056 AN: 251380 AF XY: 0.0620

Gnomad AFR exome AF: 0.0127

Gnomad AMR exome AF: 0.0357

Gnomad ASJ exome AF: 0.146

Gnomad EAS exome AF: 0.00299

Gnomad FIN exome AF: 0.0315

Gnomad NFE exome AF: 0.0818

Gnomad OTH exome AF: 0.0740

GnomAD4 exome AF: 0.0689 AC: 100601 AN: 1459548 Hom.: 3957 Cov.: 30 AF XY: 0.0690 AC XY: 50146 AN XY: 726272

African (AFR) AF: 0.0125 AC: 419 AN: 33448

American (AMR) AF: 0.0383 AC: 1715 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.145 AC: 3795 AN: 26120

East Asian (EAS) AF: 0.00159 AC: 63 AN: 39680

South Asian (SAS) AF: 0.0525 AC: 4527 AN: 86222

European-Finnish (FIN) AF: 0.0330 AC: 1763 AN: 53414

Middle Eastern (MID) AF: 0.0866 AC: 499 AN: 5760

European-Non Finnish (NFE) AF: 0.0755 AC: 83770 AN: 1109846

Other (OTH) AF: 0.0671 AC: 4050 AN: 60334

GnomAD4 genome AF: 0.0531 AC: 8082 AN: 152326 Hom.: 301 Cov.: 33 AF XY: 0.0508 AC XY: 3783 AN XY: 74476

African (AFR) AF: 0.0131 AC: 545 AN: 41582

American (AMR) AF: 0.0520 AC: 796 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.136 AC: 473 AN: 3470

East Asian (EAS) AF: 0.00232 AC: 12 AN: 5182

South Asian (SAS) AF: 0.0528 AC: 255 AN: 4830

European-Finnish (FIN) AF: 0.0339 AC: 360 AN: 10618

Middle Eastern (MID) AF: 0.0816 AC: 24 AN: 294

European-Non Finnish (NFE) AF: 0.0797 AC: 5424 AN: 68026

Other (OTH) AF: 0.0625 AC: 132 AN: 2112

Alfa AF: 0.0716 Hom.: 1399

Bravo AF: 0.0522

TwinsUK AF: 0.0709 AC: 263

ALSPAC AF: 0.0721 AC: 278

ESP6500AA AF: 0.0168 AC: 74

ESP6500EA AF: 0.0826 AC: 710

ExAC AF: 0.0606 AC: 7353

Asia WGS AF: 0.0280 AC: 97 AN: 3478

EpiCase AF: 0.0806

EpiControl AF: 0.0835

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Hepatic veno-occlusive disease-immunodeficiency syndrome (2)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	8.1
DANN	Benign	0.64
DEOGEN2	Benign	0.0048	T
Eigen	Benign	-0.97
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.095	N
LIST_S2	Benign	0.82	T
MetaRNN	Benign	0.0022	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.84	L
PhyloP100		-0.23
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.96	N
REVEL	Benign	0.16
Sift	Benign	0.48	T
Sift4G	Benign	0.43	T
Polyphen		0.046	B
Vest4		0.094
MutPred		0.77		Gain of methylation at K580 (P = 0.0439)
MPC		0.16
ClinPred		0.00030	T
GERP RS		2.7
Varity_R		0.065
gMVP		0.14
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3948463; hg19: chr2-231036860; COSMIC: COSV51250701; COSMIC: COSV51250701;