2-230185999-A-G

Variant names:

• chr2-230185999-A-G
• rs3948464
• NM_080424.4:c.1274T>C
• SP110 p.Leu425Ser

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.1274T>C​(p.Leu425Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.872 in 1,613,516 control chromosomes in the GnomAD database, including 614,159 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 0.87 (57874 hom., cov: 31)
  • Exomes 𝑓: 0.87 (556285 hom.)
• Consequence: SP110 NM_080424.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:7
• Conservation: PhyloP100: -0.354
• Publications: 58 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=1.0717378E-6).
• BP6: Variant 2-230185999-A-G is Benign according to our data. Variant chr2-230185999-A-G is described in ClinVar as Benign. ClinVar VariationId is 5539.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.975 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.1274T>C	p.Leu425Ser	missense	Exon 11 of 19	NP_536349.3	Q9HB58-6
	SP110	NM_001378442.1		c.1292T>C	p.Leu431Ser	missense	Exon 12 of 20	NP_001365371.1
	SP110	NM_001378443.1		c.1274T>C	p.Leu425Ser	missense	Exon 11 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.1274T>C	p.Leu425Ser	missense	Exon 11 of 19	ENSP00000258381.6	Q9HB58-6
	SP110	ENST00000358662.9	TSL:1	c.1274T>C	p.Leu425Ser	missense	Exon 11 of 18	ENSP00000351488.4	Q9HB58-1
	SP110	ENST00000258382.10	TSL:1	c.1274T>C	p.Leu425Ser	missense	Exon 11 of 15	ENSP00000258382.5	Q9HB58-3

Frequencies

GnomAD3 genomes AF: 0.872 AC: 132580 AN: 152068 Hom.: 57849 Cov.: 31

Gnomad AFR AF: 0.851

Gnomad AMI AF: 0.878

Gnomad AMR AF: 0.892

Gnomad ASJ AF: 0.900

Gnomad EAS AF: 0.997

Gnomad SAS AF: 0.923

Gnomad FIN AF: 0.862

Gnomad MID AF: 0.889

Gnomad NFE AF: 0.867

Gnomad OTH AF: 0.866

GnomAD2 exomes AF: 0.890 AC: 223707 AN: 251476 AF XY: 0.889

Gnomad AFR exome AF: 0.851

Gnomad AMR exome AF: 0.923

Gnomad ASJ exome AF: 0.900

Gnomad EAS exome AF: 0.998

Gnomad FIN exome AF: 0.862

Gnomad NFE exome AF: 0.865

Gnomad OTH exome AF: 0.881

GnomAD4 exome AF: 0.872 AC: 1274205 AN: 1461330 Hom.: 556285 Cov.: 44 AF XY: 0.873 AC XY: 634789 AN XY: 726990

African (AFR) AF: 0.847 AC: 28354 AN: 33466

American (AMR) AF: 0.922 AC: 41218 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.904 AC: 23631 AN: 26134

East Asian (EAS) AF: 0.999 AC: 39661 AN: 39698

South Asian (SAS) AF: 0.917 AC: 79085 AN: 86248

European-Finnish (FIN) AF: 0.858 AC: 45838 AN: 53418

Middle Eastern (MID) AF: 0.873 AC: 5036 AN: 5768

European-Non Finnish (NFE) AF: 0.862 AC: 958498 AN: 1111498

Other (OTH) AF: 0.876 AC: 52884 AN: 60376

GnomAD4 genome AF: 0.872 AC: 132661 AN: 152186 Hom.: 57874 Cov.: 31 AF XY: 0.874 AC XY: 65007 AN XY: 74402

African (AFR) AF: 0.850 AC: 35281 AN: 41496

American (AMR) AF: 0.892 AC: 13649 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.900 AC: 3120 AN: 3466

East Asian (EAS) AF: 0.997 AC: 5166 AN: 5180

South Asian (SAS) AF: 0.922 AC: 4443 AN: 4818

European-Finnish (FIN) AF: 0.862 AC: 9145 AN: 10606

Middle Eastern (MID) AF: 0.881 AC: 259 AN: 294

European-Non Finnish (NFE) AF: 0.867 AC: 58967 AN: 68002

Other (OTH) AF: 0.866 AC: 1830 AN: 2114

Alfa AF: 0.836 Hom.: 137874

Bravo AF: 0.873

Asia WGS AF: 0.942 AC: 3275 AN: 3478

EpiCase AF: 0.870

EpiControl AF: 0.866

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	Hepatic veno-occlusive disease-immunodeficiency syndrome (2)
-	1	-	Mycobacterium tuberculosis, susceptibility to (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	0.28
DANN	Benign	0.27
DEOGEN2	Benign	0.0016	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.00029	N
LIST_S2	Benign	0.10	T
MetaRNN	Benign	0.0000011	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.20	N
PhyloP100		-0.35
PrimateAI	Benign	0.21	T
PROVEAN	Benign	0.88	N
REVEL	Benign	0.035
Sift	Benign	0.82	T
Sift4G	Benign	0.53	T
Varity_R		0.025
gMVP		0.041
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs3948464;

hg19: chr2-231050715;

COSMIC: COSV107250541;