2-197402104-G-T

Variant names:

• chr2-197402104-G-T
• rs16865307
• NM_012433.4:c.2104C>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_012433.4(SF3B1):​c.2104C>A​(p.Arg702Arg) variant causes a synonymous change. The variant allele was found at a frequency of 0.00298 in 1,606,010 control chromosomes in the GnomAD database, including 100 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0066 (13 hom., cov: 32)
  • Exomes 𝑓: 0.0026 (87 hom.)
• Consequence: SF3B1 NM_012433.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 7.13
• Publications: 8 publications found

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

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.32).
• BP6: Variant 2-197402104-G-T is Benign according to our data. Variant chr2-197402104-G-T is described in ClinVar as [Benign]. Clinvar id is 788088.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00661 (1006/152214) while in subpopulation SAS AF = 0.0299 (144/4820). AF 95% confidence interval is 0.0259. There are 13 homozygotes in GnomAd4. There are 531 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1006 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SF3B1	NM_012433.4	c.2104C>A	p.Arg702Arg	synonymous_variant	Exon 15 of 25	ENST00000335508.11	NP_036565.2
SF3B1	XM_047443838.1	c.1666C>A	p.Arg556Arg	synonymous_variant	Exon 12 of 22		XP_047299794.1
SF3B1	XM_047443839.1	c.1666C>A	p.Arg556Arg	synonymous_variant	Exon 12 of 22		XP_047299795.1
SF3B1	XM_047443840.1	c.2104C>A	p.Arg702Arg	synonymous_variant	Exon 15 of 22		XP_047299796.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SF3B1	ENST00000335508.11	c.2104C>A	p.Arg702Arg	synonymous_variant	Exon 15 of 25	1	NM_012433.4	ENSP00000335321.6

Frequencies

GnomAD3 genomes AF: 0.00653 AC: 993 AN: 152096 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.0183

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00295

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00385

Gnomad SAS AF: 0.0296

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00383

GnomAD2 exomes AF: 0.00560 AC: 1383 AN: 246834 AF XY: 0.00626

Gnomad AFR exome AF: 0.0186

Gnomad AMR exome AF: 0.00116

Gnomad ASJ exome AF: 0.00273

Gnomad EAS exome AF: 0.00391

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000267

Gnomad OTH exome AF: 0.00315

GnomAD4 exome AF: 0.00260 AC: 3776 AN: 1453796 Hom.: 87 Cov.: 32 AF XY: 0.00325 AC XY: 2350 AN XY: 722374

African (AFR) AF: 0.0195 AC: 644 AN: 33076

American (AMR) AF: 0.000951 AC: 41 AN: 43102

Ashkenazi Jewish (ASJ) AF: 0.00250 AC: 65 AN: 25978

East Asian (EAS) AF: 0.00362 AC: 143 AN: 39536

South Asian (SAS) AF: 0.0278 AC: 2379 AN: 85564

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53342

Middle Eastern (MID) AF: 0.00348 AC: 20 AN: 5748

European-Non Finnish (NFE) AF: 0.000204 AC: 226 AN: 1107410

Other (OTH) AF: 0.00428 AC: 257 AN: 60040

GnomAD4 genome AF: 0.00661 AC: 1006 AN: 152214 Hom.: 13 Cov.: 32 AF XY: 0.00713 AC XY: 531 AN XY: 74422

African (AFR) AF: 0.0183 AC: 762 AN: 41530

American (AMR) AF: 0.00294 AC: 45 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3468

East Asian (EAS) AF: 0.00386 AC: 20 AN: 5186

South Asian (SAS) AF: 0.0299 AC: 144 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68012

Other (OTH) AF: 0.00664 AC: 14 AN: 2110

Alfa AF: 0.00494 Hom.: 3

Bravo AF: 0.00676

Asia WGS AF: 0.0260 AC: 89 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
CADD	Benign	9.9
DANN	Benign	0.84
PhyloP100		7.1
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.2
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs16865307; hg19: chr2-198266828;