rs3948463

chr2-230172144-C-T

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.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. 14/20 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:3
• Conservation: PhyloP100: -0.229

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SP110	NM_080424.4	c.1737G>A	p.Met579Ile	missense_variant	16/19	ENST00000258381.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SP110	ENST00000258381.11	c.1737G>A	p.Met579Ile	missense_variant	16/19	2	NM_080424.4	P1
	ENST00000628587.2	n.1049C>T		non_coding_transcript_exon_variant	3/4	5

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

GnomAD3 exomes AF: 0.0599 AC: 15056 AN: 251380 Hom.: 594 AF XY: 0.0620 AC XY: 8423 AN XY: 135858

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 SAS exome AF: 0.0541

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

Gnomad4 AFR exome AF: 0.0125

Gnomad4 AMR exome AF: 0.0383

Gnomad4 ASJ exome AF: 0.145

Gnomad4 EAS exome AF: 0.00159

Gnomad4 SAS exome AF: 0.0525

Gnomad4 FIN exome AF: 0.0330

Gnomad4 NFE exome AF: 0.0755

Gnomad4 OTH exome AF: 0.0671

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

Gnomad4 AFR AF: 0.0131

Gnomad4 AMR AF: 0.0520

Gnomad4 ASJ AF: 0.136

Gnomad4 EAS AF: 0.00232

Gnomad4 SAS AF: 0.0528

Gnomad4 FIN AF: 0.0339

Gnomad4 NFE AF: 0.0797

Gnomad4 OTH AF: 0.0625

Alfa AF: 0.0758 Hom.: 1105

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

Significance: Benign

Submissions summary: Benign:3

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 13, 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. -

not specified Benign:1

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: MAF -

Computational scores

Source: dbNSFP v4.3

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
Eigen	Benign	-0.97
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.095	N
LIST_S2	Benign	0.82	T;T
MetaRNN	Benign	0.0022	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.84	L;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.96	N;N
REVEL	Benign	0.16
Sift	Benign	0.48	T;T
Sift4G	Benign	0.43	T;T
Polyphen		0.046	B;B
Vest4		0.094
MutPred		0.77		Gain of methylation at K580 (P = 0.0439);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

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