2-197402104-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BS1 BS2

The NM_012433.4(SF3B1):c.2104C>A(p.Arg702=) variant causes a synonymous change. The variant allele was found at a frequency of 0.00298 in 1,606,010 control chromosomes in the GnomAD database, including 100 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0066 (13 hom., cov: 32)
  • Exomes 𝑓: 0.0026 (87 hom.)
• Consequence: SF3B1 NM_012433.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 7.13

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.32).
• BP6: Variant 2-197402104-G-T is Benign according to our data. Variant chr2-197402104-G-T is described in ClinVar as [Benign]. Clinvar id is 788088.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-197402104-G-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00661 (1006/152214) while in subpopulation SAS AF= 0.0299 (144/4820). AF 95% confidence interval is 0.0259. There are 13 homozygotes in gnomad4. There are 531 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 993 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SF3B1	NM_012433.4	c.2104C>A	p.Arg702=	synonymous_variant	15/25	ENST00000335508.11
SF3B1	XM_047443838.1	c.1666C>A	p.Arg556=	synonymous_variant	12/22
SF3B1	XM_047443839.1	c.1666C>A	p.Arg556=	synonymous_variant	12/22
SF3B1	XM_047443840.1	c.2104C>A	p.Arg702=	synonymous_variant	15/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SF3B1	ENST00000335508.11	c.2104C>A	p.Arg702=	synonymous_variant	15/25	1	NM_012433.4	P1

Frequencies

GnomAD3 genomes AF: 0.00653 AC: 993 AN: 152096 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.0183

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00295

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00385

Gnomad SAS AF: 0.0296

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00383

GnomAD3 exomes AF: 0.00560 AC: 1383 AN: 246834 Hom.: 25 AF XY: 0.00626 AC XY: 837 AN XY: 133602

Gnomad AFR exome AF: 0.0186

Gnomad AMR exome AF: 0.00116

Gnomad ASJ exome AF: 0.00273

Gnomad EAS exome AF: 0.00391

Gnomad SAS exome AF: 0.0300

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000267

Gnomad OTH exome AF: 0.00315

GnomAD4 exome AF: 0.00260 AC: 3776 AN: 1453796 Hom.: 87 Cov.: 32 AF XY: 0.00325 AC XY: 2350 AN XY: 722374

Gnomad4 AFR exome AF: 0.0195

Gnomad4 AMR exome AF: 0.000951

Gnomad4 ASJ exome AF: 0.00250

Gnomad4 EAS exome AF: 0.00362

Gnomad4 SAS exome AF: 0.0278

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000204

Gnomad4 OTH exome AF: 0.00428

GnomAD4 genome AF: 0.00661 AC: 1006 AN: 152214 Hom.: 13 Cov.: 32 AF XY: 0.00713 AC XY: 531 AN XY: 74422

Gnomad4 AFR AF: 0.0183

Gnomad4 AMR AF: 0.00294

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00386

Gnomad4 SAS AF: 0.0299

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.00664

Alfa AF: 0.00289 Hom.: 0

Bravo AF: 0.00676

Asia WGS AF: 0.0260 AC: 89 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
Cadd	Benign	9.9
Dann	Benign	0.84
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.2

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: rs16865307; hg19: chr2-198266828;