chr2-197392312-A-G

Variant names:

• chr2-197392312-A-G
• rs150226353
• NM_012433.4:c.3906T>C

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BS1 BS2

The NM_012433.4(SF3B1):​c.3906T>C​(p.Tyr1302Tyr) 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
• Publications: 2 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 -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 VariationId is 788087.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 181 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.3906T>C	p.Tyr1302Tyr	synonymous	Exon 25 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.3906T>C	p.Tyr1302Tyr	synonymous	Exon 25 of 25	ENSP00000335321.6	O75533-1
	SF3B1	ENST00000929354.1		c.3903T>C	p.Tyr1301Tyr	synonymous	Exon 25 of 25	ENSP00000599413.1
	SF3B1	ENST00000929356.1		c.3825T>C	p.Tyr1275Tyr	synonymous	Exon 25 of 25	ENSP00000599415.1

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

GnomAD2 exomes AF: 0.00392 AC: 935 AN: 238356 AF XY: 0.00493

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 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

African (AFR) AF: 0.0000856 AC: 2 AN: 23376

American (AMR) AF: 0.0000496 AC: 2 AN: 40290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22510

East Asian (EAS) AF: 0.00363 AC: 136 AN: 37436

South Asian (SAS) AF: 0.0285 AC: 2093 AN: 73324

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53042

Middle Eastern (MID) AF: 0.000626 AC: 3 AN: 4794

European-Non Finnish (NFE) AF: 0.0000119 AC: 8 AN: 670296

Other (OTH) AF: 0.00235 AC: 103 AN: 43882

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

African (AFR) AF: 0.0000962 AC: 4 AN: 41572

American (AMR) AF: 0.00 AC: 0 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00386 AC: 20 AN: 5188

South Asian (SAS) AF: 0.0309 AC: 149 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68040

Other (OTH) AF: 0.00284 AC: 6 AN: 2112

Alfa AF: 0.000134 Hom.: 0

Bravo AF: 0.000344

Asia WGS AF: 0.0280 AC: 96 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	6.2
DANN	Benign	0.49
PhyloP100		3.3
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: rs150226353; hg19: chr2-198257036;