rs3769838

Variant names:

• chr2-230211476-T-C
• rs3769838
• NM_080424.4:c.745A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_080424.4(SP110):​c.745A>G​(p.Met249Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000719 in 1,598,504 control chromosomes in the GnomAD database, including 12 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 0.00062 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00073 (11 hom.)
• Consequence: SP110 NM_080424.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.738
• 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=0.0033704638).
• BP6: Variant 2-230211476-T-C is Benign according to our data. Variant chr2-230211476-T-C is described in ClinVar as Benign. ClinVar VariationId is 712934.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000624 (95/152304) while in subpopulation EAS AF = 0.016 (83/5174). AF 95% confidence interval is 0.0133. There are 1 homozygotes in GnomAd4. There are 52 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 11 AR gene

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.745A>G	p.Met249Val	missense	Exon 6 of 19	NP_536349.3	Q9HB58-6
	SP110	NM_001378442.1		c.763A>G	p.Met255Val	missense	Exon 7 of 20	NP_001365371.1
	SP110	NM_001378443.1		c.745A>G	p.Met249Val	missense	Exon 6 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.745A>G	p.Met249Val	missense	Exon 6 of 19	ENSP00000258381.6	Q9HB58-6
	SP110	ENST00000358662.9	TSL:1	c.745A>G	p.Met249Val	missense	Exon 6 of 18	ENSP00000351488.4	Q9HB58-1
	SP110	ENST00000258382.10	TSL:1	c.745A>G	p.Met249Val	missense	Exon 6 of 15	ENSP00000258382.5	Q9HB58-3

Frequencies

GnomAD3 genomes AF: 0.000624 AC: 95 AN: 152186 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0160

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00103 AC: 258 AN: 251338 AF XY: 0.000883

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0123

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000158

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000729 AC: 1054 AN: 1446200 Hom.: 11 Cov.: 27 AF XY: 0.000713 AC XY: 514 AN XY: 720548

African (AFR) AF: 0.0000302 AC: 1 AN: 33164

American (AMR) AF: 0.000112 AC: 5 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26046

East Asian (EAS) AF: 0.0230 AC: 913 AN: 39628

South Asian (SAS) AF: 0.000268 AC: 23 AN: 85912

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.000348 AC: 2 AN: 5742

European-Non Finnish (NFE) AF: 0.0000765 AC: 84 AN: 1097662

Other (OTH) AF: 0.000434 AC: 26 AN: 59936

GnomAD4 genome AF: 0.000624 AC: 95 AN: 152304 Hom.: 1 Cov.: 32 AF XY: 0.000698 AC XY: 52 AN XY: 74486

African (AFR) AF: 0.00 AC: 0 AN: 41576

American (AMR) AF: 0.00 AC: 0 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.0160 AC: 83 AN: 5174

South Asian (SAS) AF: 0.000828 AC: 4 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68012

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000655 Hom.: 4

Bravo AF: 0.000574

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00122 AC: 148

Asia WGS AF: 0.00549 AC: 19 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000237

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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.015
DANN	Benign	0.79
DEOGEN2	Benign	0.0011	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.00058	N
LIST_S2	Benign	0.53	T
MetaRNN	Benign	0.0034	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.26	N
PhyloP100		-0.74
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.0	N
REVEL	Benign	0.030
Sift	Benign	0.27	T
Sift4G	Benign	0.57	T
Polyphen		0.0010	B
Vest4		0.028
MVP		0.13
MPC		0.14
ClinPred		0.0029	T
GERP RS		2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.043
gMVP		0.096
Mutation Taster		=109/91	polymorphism

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: rs3769838; hg19: chr2-231076191; COSMIC: COSV51275833; COSMIC: COSV51275833;