chr2-197398035-A-G

Variant names:

• chr2-197398035-A-G
• rs111736429
• NM_012433.4:c.3216T>C

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP6_Very_Strong BP7 BS1 BS2

The NM_012433.4(SF3B1):​c.3216T>C​(p.Ala1072Ala) 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. Variant has been reported in ClinVar as Likely 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/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.86
• Publications: 6 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]

SF3B1 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• BP6: Variant 2-197398035-A-G is Benign according to our data. Variant chr2-197398035-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 715640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 696 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012433.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SF3B1	NM_012433.4	MANE Select	c.3216T>C	p.Ala1072Ala	synonymous	Exon 22 of 25	NP_036565.2	O75533-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SF3B1	ENST00000335508.11	TSL:1 MANE Select	c.3216T>C	p.Ala1072Ala	synonymous	Exon 22 of 25	ENSP00000335321.6	O75533-1
	SF3B1	ENST00000929354.1		c.3213T>C	p.Ala1071Ala	synonymous	Exon 22 of 25	ENSP00000599413.1
	SF3B1	ENST00000929356.1		c.3135T>C	p.Ala1045Ala	synonymous	Exon 22 of 25	ENSP00000599415.1

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

GnomAD2 exomes AF: 0.00469 AC: 1179 AN: 251384 AF XY: 0.00497

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 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

African (AFR) AF: 0.00128 AC: 43 AN: 33468

American (AMR) AF: 0.00177 AC: 79 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00172 AC: 45 AN: 26130

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39668

South Asian (SAS) AF: 0.00525 AC: 453 AN: 86236

European-Finnish (FIN) AF: 0.00316 AC: 169 AN: 53404

Middle Eastern (MID) AF: 0.00659 AC: 38 AN: 5764

European-Non Finnish (NFE) AF: 0.00799 AC: 8882 AN: 1111398

Other (OTH) AF: 0.00558 AC: 337 AN: 60364

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

African (AFR) AF: 0.00132 AC: 55 AN: 41570

American (AMR) AF: 0.00281 AC: 43 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00560 AC: 27 AN: 4820

European-Finnish (FIN) AF: 0.00198 AC: 21 AN: 10614

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

European-Non Finnish (NFE) AF: 0.00784 AC: 533 AN: 68024

Other (OTH) AF: 0.00190 AC: 4 AN: 2110

Alfa AF: 0.00486 Hom.: 3

Bravo AF: 0.00433

Asia WGS AF: 0.000578 AC: 2 AN: 3474

EpiCase AF: 0.00611

EpiControl AF: 0.00640

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	12
DANN	Benign	0.72
PhyloP100		2.9
Mutation Taster		=87/13	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: rs111736429; hg19: chr2-198262759; COSMIC: COSV59214083; COSMIC: COSV59214083;