2-197392351-G-A

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.3867C>T(p.Asn1289=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00864 in 1,534,372 control chromosomes in the GnomAD database, including 69 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0062 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0089 (63 hom.)
• Consequence: SF3B1 NM_012433.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.888

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=-0.47).
• BP6: Variant 2-197392351-G-A is Benign according to our data. Variant chr2-197392351-G-A is described in ClinVar as [Benign]. Clinvar id is 790342.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-197392351-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.888 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00625 (951/152208) while in subpopulation NFE AF= 0.00991 (674/68012). AF 95% confidence interval is 0.00929. There are 6 homozygotes in gnomad4. There are 447 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 951 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SF3B1	NM_012433.4	c.3867C>T	p.Asn1289=	synonymous_variant	25/25	ENST00000335508.11
SF3B1	XM_047443838.1	c.3429C>T	p.Asn1143=	synonymous_variant	22/22
SF3B1	XM_047443839.1	c.3429C>T	p.Asn1143=	synonymous_variant	22/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SF3B1	ENST00000335508.11	c.3867C>T	p.Asn1289=	synonymous_variant	25/25	1	NM_012433.4	P1

Frequencies

GnomAD3 genomes AF: 0.00625 AC: 951 AN: 152090 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00135

Gnomad AMI AF: 0.0680

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00806

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00983

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00991

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00599 AC: 1498 AN: 250280 Hom.: 7 AF XY: 0.00593 AC XY: 802 AN XY: 135286

Gnomad AFR exome AF: 0.00123

Gnomad AMR exome AF: 0.000876

Gnomad ASJ exome AF: 0.00805

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.000428

Gnomad FIN exome AF: 0.0102

Gnomad NFE exome AF: 0.00973

Gnomad OTH exome AF: 0.00508

GnomAD4 exome AF: 0.00890 AC: 12301 AN: 1382164 Hom.: 63 Cov.: 24 AF XY: 0.00856 AC XY: 5925 AN XY: 692322

Gnomad4 AFR exome AF: 0.00113

Gnomad4 AMR exome AF: 0.000990

Gnomad4 ASJ exome AF: 0.00686

Gnomad4 EAS exome AF: 0.000102

Gnomad4 SAS exome AF: 0.000332

Gnomad4 FIN exome AF: 0.00804

Gnomad4 NFE exome AF: 0.0108

Gnomad4 OTH exome AF: 0.00691

GnomAD4 genome AF: 0.00625 AC: 951 AN: 152208 Hom.: 6 Cov.: 32 AF XY: 0.00601 AC XY: 447 AN XY: 74410

Gnomad4 AFR AF: 0.00135

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.00806

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00983

Gnomad4 NFE AF: 0.00991

Gnomad4 OTH AF: 0.00332

Alfa AF: 0.00804 Hom.: 2

Bravo AF: 0.00597

Asia WGS AF: 0.00115 AC: 4 AN: 3476

EpiCase AF: 0.00861

EpiControl AF: 0.00784

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	-0.47
Cadd	Benign	6.4
Dann	Benign	0.68

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: rs78516934; hg19: chr2-198257075; COSMIC: COSV59220870; COSMIC: COSV59220870;