2-197402138-A-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_012433.4(SF3B1):c.2078-8T>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00924 in 1,593,392 control chromosomes in the GnomAD database, including 170 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0092 (14 hom., cov: 32)
  • Exomes 𝑓: 0.0092 (156 hom.)
• Consequence: SF3B1 NM_012433.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.06590
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.59

Genes affected

SF3B1 (HGNC:10768): (splicing factor 3b subunit 1) This gene encodes subunit 1 of the splicing factor 3b protein complex. Splicing factor 3b, together with splicing factor 3a and a 12S RNA unit, forms the U2 small nuclear ribonucleoproteins complex (U2 snRNP). The splicing factor 3b/3a complex binds pre-mRNA upstream of the intron's branch site in a sequence independent manner and may anchor the U2 snRNP to the pre-mRNA. Splicing factor 3b is also a component of the minor U12-type spliceosome. The carboxy-terminal two-thirds of subunit 1 have 22 non-identical, tandem HEAT repeats that form rod-like, helical structures. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 2-197402138-A-T is Benign according to our data. Variant chr2-197402138-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 3041954.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-197402138-A-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00925 (1408/152264) while in subpopulation SAS AF= 0.0379 (183/4830). AF 95% confidence interval is 0.0334. There are 14 homozygotes in gnomad4. There are 703 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 1410 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SF3B1	NM_012433.4	c.2078-8T>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000335508.11
SF3B1	XM_047443838.1	c.1640-8T>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
SF3B1	XM_047443839.1	c.1640-8T>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
SF3B1	XM_047443840.1	c.2078-8T>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SF3B1	ENST00000335508.11	c.2078-8T>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_012433.4	P1

Frequencies

GnomAD3 genomes AF: 0.00927 AC: 1410 AN: 152146 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.0110

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00819

Gnomad ASJ AF: 0.0124

Gnomad EAS AF: 0.00115

Gnomad SAS AF: 0.0383

Gnomad FIN AF: 0.00217

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.00795

Gnomad OTH AF: 0.0105

GnomAD3 exomes AF: 0.0113 AC: 2701 AN: 239852 Hom.: 38 AF XY: 0.0123 AC XY: 1600 AN XY: 130074

Gnomad AFR exome AF: 0.0118

Gnomad AMR exome AF: 0.00485

Gnomad ASJ exome AF: 0.0125

Gnomad EAS exome AF: 0.000842

Gnomad SAS exome AF: 0.0385

Gnomad FIN exome AF: 0.00434

Gnomad NFE exome AF: 0.00882

Gnomad OTH exome AF: 0.00995

GnomAD4 exome AF: 0.00924 AC: 13320 AN: 1441128 Hom.: 156 Cov.: 32 AF XY: 0.0101 AC XY: 7196 AN XY: 714596

Gnomad4 AFR exome AF: 0.0126

Gnomad4 AMR exome AF: 0.00482

Gnomad4 ASJ exome AF: 0.0117

Gnomad4 EAS exome AF: 0.00158

Gnomad4 SAS exome AF: 0.0387

Gnomad4 FIN exome AF: 0.00391

Gnomad4 NFE exome AF: 0.00737

Gnomad4 OTH exome AF: 0.0112

GnomAD4 genome AF: 0.00925 AC: 1408 AN: 152264 Hom.: 14 Cov.: 32 AF XY: 0.00944 AC XY: 703 AN XY: 74460

Gnomad4 AFR AF: 0.0110

Gnomad4 AMR AF: 0.00818

Gnomad4 ASJ AF: 0.0124

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.0379

Gnomad4 FIN AF: 0.00217

Gnomad4 NFE AF: 0.00795

Gnomad4 OTH AF: 0.0109

Alfa AF: 0.00859 Hom.: 2

Bravo AF: 0.00846

Asia WGS AF: 0.0210 AC: 72 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

SF3B1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 25, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
Cadd	Benign	12
Dann	Benign	0.79
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.066
dbscSNV1_RF	Benign	0.22
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

Publications

LitVar

Other links and lift over

dbSNP: rs3764989; hg19: chr2-198266862;