2-197393071-T-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_012433.4(SF3B1):c.3657A>G(p.Val1219=) 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 1,611,676 control chromosomes in the GnomAD database, including 375,213 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.71 (39045 hom., cov: 32)
  • Exomes 𝑓: 0.68 (336168 hom.)
• Consequence: SF3B1 NM_012433.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.231

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 2-197393071-T-C is Benign according to our data. Variant chr2-197393071-T-C is described in ClinVar as [Benign]. Clinvar id is 1250652.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-197393071-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.231 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.829 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SF3B1	NM_012433.4	c.3657A>G	p.Val1219=	synonymous_variant	24/25	ENST00000335508.11
SF3B1	XM_047443838.1	c.3219A>G	p.Val1073=	synonymous_variant	21/22
SF3B1	XM_047443839.1	c.3219A>G	p.Val1073=	synonymous_variant	21/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SF3B1	ENST00000335508.11	c.3657A>G	p.Val1219=	synonymous_variant	24/25	1	NM_012433.4	P1

Frequencies

GnomAD3 genomes AF: 0.710 AC: 107863 AN: 151992 Hom.: 39007 Cov.: 32

Gnomad AFR AF: 0.836

Gnomad AMI AF: 0.714

Gnomad AMR AF: 0.650

Gnomad ASJ AF: 0.750

Gnomad EAS AF: 0.553

Gnomad SAS AF: 0.747

Gnomad FIN AF: 0.571

Gnomad MID AF: 0.861

Gnomad NFE AF: 0.674

Gnomad OTH AF: 0.727

GnomAD3 exomes AF: 0.658 AC: 165437 AN: 251276 Hom.: 56094 AF XY: 0.670 AC XY: 90958 AN XY: 135820

Gnomad AFR exome AF: 0.840

Gnomad AMR exome AF: 0.496

Gnomad ASJ exome AF: 0.753

Gnomad EAS exome AF: 0.533

Gnomad SAS exome AF: 0.755

Gnomad FIN exome AF: 0.577

Gnomad NFE exome AF: 0.681

Gnomad OTH exome AF: 0.698

GnomAD4 exome AF: 0.676 AC: 986242 AN: 1459566 Hom.: 336168 Cov.: 36 AF XY: 0.679 AC XY: 493024 AN XY: 726240

Gnomad4 AFR exome AF: 0.847

Gnomad4 AMR exome AF: 0.518

Gnomad4 ASJ exome AF: 0.750

Gnomad4 EAS exome AF: 0.636

Gnomad4 SAS exome AF: 0.755

Gnomad4 FIN exome AF: 0.579

Gnomad4 NFE exome AF: 0.674

Gnomad4 OTH exome AF: 0.686

GnomAD4 genome AF: 0.710 AC: 107954 AN: 152110 Hom.: 39045 Cov.: 32 AF XY: 0.706 AC XY: 52531 AN XY: 74354

Gnomad4 AFR AF: 0.836

Gnomad4 AMR AF: 0.649

Gnomad4 ASJ AF: 0.750

Gnomad4 EAS AF: 0.554

Gnomad4 SAS AF: 0.748

Gnomad4 FIN AF: 0.571

Gnomad4 NFE AF: 0.674

Gnomad4 OTH AF: 0.727

Alfa AF: 0.690 Hom.: 19655

Bravo AF: 0.717

Asia WGS AF: 0.655 AC: 2280 AN: 3478

EpiCase AF: 0.707

EpiControl AF: 0.709

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

SF3B1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 17, 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). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 05, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
Cadd	Benign	8.5
Dann	Benign	0.78
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: rs4685; hg19: chr2-198257795; COSMIC: COSV59206298; COSMIC: COSV59206298;