rs788018

Positions:

• chr2-197400802-A-G
• chr2-197400802-A-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_012433.4(SF3B1):​c.2631T>C​(p.Gly877=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.679 in 1,611,526 control chromosomes in the GnomAD database, including 375,202 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.71 (38925 hom., cov: 31)
  • Exomes 𝑓: 0.68 (336277 hom.)
• Consequence: SF3B1 NM_012433.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.494

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 2-197400802-A-G is Benign according to our data. Variant chr2-197400802-A-G is described in ClinVar as [Benign]. Clinvar id is 1228123.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-197400802-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.494 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.827 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SF3B1	NM_012433.4	c.2631T>C	p.Gly877=	synonymous_variant	18/25	ENST00000335508.11	NP_036565.2
SF3B1	XM_047443838.1	c.2193T>C	p.Gly731=	synonymous_variant	15/22		XP_047299794.1
SF3B1	XM_047443839.1	c.2193T>C	p.Gly731=	synonymous_variant	15/22		XP_047299795.1
SF3B1	XM_047443840.1	c.2631T>C	p.Gly877=	synonymous_variant	18/22		XP_047299796.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SF3B1	ENST00000335508.11	c.2631T>C	p.Gly877=	synonymous_variant	18/25	1	NM_012433.4	ENSP00000335321	P1
SF3B1	ENST00000470268.2	n.4515T>C		non_coding_transcript_exon_variant	17/24	2
SF3B1	ENST00000652026.1	c.*3698T>C		3_prime_UTR_variant, NMD_transcript_variant	18/25			ENSP00000498652
SF3B1	ENST00000652738.1	c.*2890T>C		3_prime_UTR_variant, NMD_transcript_variant	19/26			ENSP00000499119

Frequencies

GnomAD3 genomes AF: 0.709 AC: 107688 AN: 151906 Hom.: 38887 Cov.: 31

Gnomad AFR AF: 0.834

Gnomad AMI AF: 0.714

Gnomad AMR AF: 0.649

Gnomad ASJ AF: 0.746

Gnomad EAS AF: 0.547

Gnomad SAS AF: 0.746

Gnomad FIN AF: 0.571

Gnomad MID AF: 0.861

Gnomad NFE AF: 0.674

Gnomad OTH AF: 0.726

GnomAD3 exomes AF: 0.658 AC: 165154 AN: 251076 Hom.: 55958 AF XY: 0.669 AC XY: 90834 AN XY: 135718

Gnomad AFR exome AF: 0.838

Gnomad AMR exome AF: 0.495

Gnomad ASJ exome AF: 0.750

Gnomad EAS exome AF: 0.526

Gnomad SAS exome AF: 0.757

Gnomad FIN exome AF: 0.577

Gnomad NFE exome AF: 0.681

Gnomad OTH exome AF: 0.698

GnomAD4 exome AF: 0.676 AC: 986349 AN: 1459502 Hom.: 336277 Cov.: 35 AF XY: 0.679 AC XY: 493158 AN XY: 726262

Gnomad4 AFR exome AF: 0.845

Gnomad4 AMR exome AF: 0.517

Gnomad4 ASJ exome AF: 0.746

Gnomad4 EAS exome AF: 0.631

Gnomad4 SAS exome AF: 0.755

Gnomad4 FIN exome AF: 0.579

Gnomad4 NFE exome AF: 0.674

Gnomad4 OTH exome AF: 0.685

GnomAD4 genome AF: 0.709 AC: 107780 AN: 152024 Hom.: 38925 Cov.: 31 AF XY: 0.706 AC XY: 52437 AN XY: 74294

Gnomad4 AFR AF: 0.834

Gnomad4 AMR AF: 0.649

Gnomad4 ASJ AF: 0.746

Gnomad4 EAS AF: 0.549

Gnomad4 SAS AF: 0.747

Gnomad4 FIN AF: 0.571

Gnomad4 NFE AF: 0.674

Gnomad4 OTH AF: 0.725

Alfa AF: 0.694 Hom.: 27804

Bravo AF: 0.716

Asia WGS AF: 0.652 AC: 2269 AN: 3478

EpiCase AF: 0.708

EpiControl AF: 0.709

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 01, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

SF3B1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 18, 2019

This variant is classified as 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	-0.53
CADD	Benign	8.9
DANN	Benign	0.77
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs788018; hg19: chr2-198265526; COSMIC: COSV59206309; COSMIC: COSV59206309;