2-197392312-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.3906T>C(p.Tyr1302=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00225 in 1,121,274 control chromosomes in the GnomAD database, including 72 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0012 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (67 hom.)
• Consequence: SF3B1 NM_012433.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.25

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=-0.55).
• BP6: Variant 2-197392312-A-G is Benign according to our data. Variant chr2-197392312-A-G is described in ClinVar as [Benign]. Clinvar id is 788087.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-197392312-A-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=3.25 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00119 (181/152324) while in subpopulation SAS AF= 0.0309 (149/4826). AF 95% confidence interval is 0.0268. There are 5 homozygotes in gnomad4. There are 132 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 174 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SF3B1	NM_012433.4	c.3906T>C	p.Tyr1302=	synonymous_variant	25/25	ENST00000335508.11
SF3B1	XM_047443838.1	c.3468T>C	p.Tyr1156=	synonymous_variant	22/22
SF3B1	XM_047443839.1	c.3468T>C	p.Tyr1156=	synonymous_variant	22/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SF3B1	ENST00000335508.11	c.3906T>C	p.Tyr1302=	synonymous_variant	25/25	1	NM_012433.4	P1

Frequencies

GnomAD3 genomes AF: 0.00114 AC: 174 AN: 152206 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00385

Gnomad SAS AF: 0.0306

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00392 AC: 935 AN: 238356 Hom.: 20 AF XY: 0.00493 AC XY: 635 AN XY: 128700

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000972

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00406

Gnomad SAS exome AF: 0.0309

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000364

Gnomad OTH exome AF: 0.00208

GnomAD4 exome AF: 0.00242 AC: 2347 AN: 968950 Hom.: 67 Cov.: 13 AF XY: 0.00332 AC XY: 1666 AN XY: 502542

Gnomad4 AFR exome AF: 0.0000856

Gnomad4 AMR exome AF: 0.0000496

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00363

Gnomad4 SAS exome AF: 0.0285

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000119

Gnomad4 OTH exome AF: 0.00235

GnomAD4 genome AF: 0.00119 AC: 181 AN: 152324 Hom.: 5 Cov.: 32 AF XY: 0.00177 AC XY: 132 AN XY: 74484

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00386

Gnomad4 SAS AF: 0.0309

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.000134 Hom.: 0

Bravo AF: 0.000344

Asia WGS AF: 0.0280 AC: 96 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

Jul 27, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
Cadd	Benign	6.2
Dann	Benign	0.49

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: rs150226353; hg19: chr2-198257036;