rs4685

Variant names:

• chr2-197393071-T-A
• rs4685
• NM_012433.4:c.3657A>T

Your query was ambiguous. Multiple possible variants found:

• chr2-197393071-T-A
• chr2-197393071-T-C
• chr2-197393071-T-G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP7

The NM_012433.4(SF3B1):​c.3657A>T​(p.Val1219Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. V1219V) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SF3B1 NM_012433.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.231
• Publications: 56 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP7: Synonymous conserved (PhyloP=0.231 with no splicing effect.

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.3657A>T	p.Val1219Val	synonymous	Exon 24 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.3657A>T	p.Val1219Val	synonymous	Exon 24 of 25	ENSP00000335321.6	O75533-1
	SF3B1	ENST00000929354.1		c.3654A>T	p.Val1218Val	synonymous	Exon 24 of 25	ENSP00000599413.1
	SF3B1	ENST00000929356.1		c.3576A>T	p.Val1192Val	synonymous	Exon 24 of 25	ENSP00000599415.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 19655

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.23
CADD	Benign	8.0
DANN	Benign	0.76
PhyloP100		0.23
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs4685; hg19: chr2-198257795;