chr2-230172840-T-A

Variant names:

• chr2-230172840-T-A
• rs201034113
• NM_080424.4:c.1706+4A>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_080424.4(SP110):​c.1706+4A>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000774 in 1,600,012 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00071 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00078 (1 hom.)
• Consequence: SP110 NM_080424.4 splice_region, intron
• Scores: Splicing: ADA: 0.3810
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.0490
• Publications: 0 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), Orphanet, ClinGen, Ambry Genetics

ENSG00000225963 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 2-230172840-T-A is Benign according to our data. Variant chr2-230172840-T-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 334899.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000709 (108/152256) while in subpopulation NFE AF = 0.00107 (73/67996). AF 95% confidence interval is 0.000876. There are 0 homozygotes in GnomAd4. There are 61 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SP110	NM_080424.4	MANE Select	c.1706+4A>T		splice_region intron	N/A	NP_536349.3
	SP110	NM_001378442.1		c.1724+4A>T		splice_region intron	N/A	NP_001365371.1
	SP110	NM_001378443.1		c.1706+4A>T		splice_region intron	N/A	NP_001365372.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SP110	ENST00000258381.11	TSL:2 MANE Select	c.1706+4A>T		splice_region intron	N/A	ENSP00000258381.6
	SP110	ENST00000358662.9	TSL:1	c.1706+4A>T		splice_region intron	N/A	ENSP00000351488.4
	ENSG00000225963	ENST00000454058.4	TSL:5	n.1165+647T>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.000710 AC: 108 AN: 152138 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00207

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00107

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000745 AC: 187 AN: 251074 AF XY: 0.000693

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00217

Gnomad NFE exome AF: 0.000899

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.000781 AC: 1130 AN: 1447756 Hom.: 1 Cov.: 28 AF XY: 0.000792 AC XY: 571 AN XY: 721240

African (AFR) AF: 0.0000302 AC: 1 AN: 33152

American (AMR) AF: 0.000425 AC: 19 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.0000767 AC: 2 AN: 26064

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39628

South Asian (SAS) AF: 0.000605 AC: 52 AN: 85980

European-Finnish (FIN) AF: 0.00253 AC: 135 AN: 53406

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5732

European-Non Finnish (NFE) AF: 0.000795 AC: 874 AN: 1099170

Other (OTH) AF: 0.000751 AC: 45 AN: 59916

GnomAD4 genome AF: 0.000709 AC: 108 AN: 152256 Hom.: 0 Cov.: 32 AF XY: 0.000819 AC XY: 61 AN XY: 74448

African (AFR) AF: 0.0000481 AC: 2 AN: 41550

American (AMR) AF: 0.000458 AC: 7 AN: 15300

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

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4822

European-Finnish (FIN) AF: 0.00207 AC: 22 AN: 10614

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

European-Non Finnish (NFE) AF: 0.00107 AC: 73 AN: 67996

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.00118 Hom.: 0

Bravo AF: 0.000502

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000474

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Hepatic veno-occlusive disease-immunodeficiency syndrome (2)
-	-	1	SP110-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	12
DANN	Benign	0.86
PhyloP100		0.049
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.38
dbscSNV1_RF	Benign	0.35
SpliceAI score (max)		0.29		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.29		Position offset: 4

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs201034113; hg19: chr2-231037556;