dbSNP rs387907185: SF3B4:p.Met1? (chr1-149927759-T-C) – ACMG Classification: Likely_pathogenic (8 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1_StrongPM2PP5_Moderate

The NM_005850.5(SF3B4):c.1A>G(p.Met1?) variant causes a start lost change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SF3B4
NM_005850.5 start_lost

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:3

Conservation

PhyloP100: 6.21

Publications

7 publications found

Variant links:

Genes affected

SF3B4 (HGNC:10771): (splicing factor 3b subunit 4) This gene encodes one of four subunits of the splicing factor 3B. The protein encoded by this gene cross-links to a region in the pre-mRNA immediately upstream of the branchpoint sequence in pre-mRNA in the prespliceosomal complex A. It also may be involved in the assembly of the B, C and E spliceosomal complexes. In addition to RNA-binding activity, this protein interacts directly and highly specifically with subunit 2 of the splicing factor 3B. This protein contains two N-terminal RNA-recognition motifs (RRMs), consistent with the observation that it binds directly to pre-mRNA. [provided by RefSeq, Jul 2008]

SF3B4 Gene-Disease associations (from GenCC):

Nager acrofacial dysostosis
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Orphanet, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
SF3B4-related acrofacial dysostosis
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
acrofacial dysostosis Rodriguez type
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

SF3B4 links:

ENSG00000305630 (HGNC:):

ENSG00000305630 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PVS1

Start lost variant, next in-frame start position is after 4 pathogenic variants. Next in-frame start position is after 44 codons. Genomic position: 149927199. Lost 0.102 part of the original CDS.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 1-149927759-T-C is Pathogenic according to our data. Variant chr1-149927759-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 31650.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005850.5. 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
	SF3B4	NM_005850.5	MANE Select	c.1A>G	p.Met1?	start_lost	Exon 1 of 6	NP_005841.1	Q15427

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SF3B4	ENST00000271628.9	TSL:1 MANE Select	c.1A>G	p.Met1?	start_lost	Exon 1 of 6	ENSP00000271628.8	Q15427
SF3B4	ENST00000940764.1		c.1A>G	p.Met1?	start_lost	Exon 1 of 6	ENSP00000610823.1
SF3B4	ENST00000940765.1		c.1A>G	p.Met1?	start_lost	Exon 1 of 6	ENSP00000610824.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1400858

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

691114

African (AFR)

AF:

0.00

AC:

AN:

31638

American (AMR)

AF:

0.00

AC:

AN:

35986

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25186

East Asian (EAS)

AF:

0.00

AC:

AN:

35818

South Asian (SAS)

AF:

0.00

AC:

AN:

79330

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49322

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5698

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1079824

Other (OTH)

AF:

0.00

AC:

AN:

58056

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Nager syndrome (2)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.15

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.21

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.90

M_CAP

Pathogenic

0.78

MetaRNN

Pathogenic

0.99

MetaSVM

Benign

-0.96

PhyloP100

6.2

PROVEAN

Uncertain

-3.4

REVEL

Uncertain

0.52

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.96

Vest4

0.96

MutPred

0.97

Gain of catalytic residue at M1 (P = 0.1295)

MVP

0.85

ClinPred

1.0

GERP RS

5.1

PromoterAI

-0.44

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.95

gMVP

0.88

Mutation Taster

=3/197

disease causing (ClinVar)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over