2-197398035-A-G

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BS1 BS2

The NM_012433.4(SF3B1):c.3216T>C(p.Ala1072=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00666 in 1,613,462 control chromosomes in the GnomAD database, including 49 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0046 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0069 (46 hom.)
• Consequence: SF3B1 NM_012433.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.86

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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 2-197398035-A-G is Benign according to our data. Variant chr2-197398035-A-G is described in ClinVar as [Benign]. Clinvar id is 715640.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=2.86 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00457 (696/152312) while in subpopulation NFE AF= 0.00784 (533/68024). AF 95% confidence interval is 0.00729. There are 3 homozygotes in gnomad4. There are 314 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 696 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SF3B1	NM_012433.4	c.3216T>C	p.Ala1072=	synonymous_variant	22/25	ENST00000335508.11
SF3B1	XM_047443838.1	c.2778T>C	p.Ala926=	synonymous_variant	19/22
SF3B1	XM_047443839.1	c.2778T>C	p.Ala926=	synonymous_variant	19/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SF3B1	ENST00000335508.11	c.3216T>C	p.Ala1072=	synonymous_variant	22/25	1	NM_012433.4	P1

Frequencies

GnomAD3 genomes AF: 0.00457 AC: 696 AN: 152194 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00133

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.00281

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00560

Gnomad FIN AF: 0.00198

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00783

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.00469 AC: 1179 AN: 251384 Hom.: 2 AF XY: 0.00497 AC XY: 675 AN XY: 135870

Gnomad AFR exome AF: 0.00117

Gnomad AMR exome AF: 0.00139

Gnomad ASJ exome AF: 0.00159

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00487

Gnomad FIN exome AF: 0.00291

Gnomad NFE exome AF: 0.00755

Gnomad OTH exome AF: 0.00424

GnomAD4 exome AF: 0.00688 AC: 10047 AN: 1461150 Hom.: 46 Cov.: 30 AF XY: 0.00684 AC XY: 4972 AN XY: 726940

Gnomad4 AFR exome AF: 0.00128

Gnomad4 AMR exome AF: 0.00177

Gnomad4 ASJ exome AF: 0.00172

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00525

Gnomad4 FIN exome AF: 0.00316

Gnomad4 NFE exome AF: 0.00799

Gnomad4 OTH exome AF: 0.00558

GnomAD4 genome AF: 0.00457 AC: 696 AN: 152312 Hom.: 3 Cov.: 32 AF XY: 0.00422 AC XY: 314 AN XY: 74484

Gnomad4 AFR AF: 0.00132

Gnomad4 AMR AF: 0.00281

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00560

Gnomad4 FIN AF: 0.00198

Gnomad4 NFE AF: 0.00784

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.00495 Hom.: 3

Bravo AF: 0.00433

Asia WGS AF: 0.000578 AC: 2 AN: 3474

EpiCase AF: 0.00611

EpiControl AF: 0.00640

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

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
Cadd	Benign	12
Dann	Benign	0.72

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: rs111736429; hg19: chr2-198262759; COSMIC: COSV59214083; COSMIC: COSV59214083;