rs782357237

Variant names:

• chr1-149923867-CG-C
• rs782357237
• NM_005850.5:c.1060delC

Your query was ambiguous. Multiple possible variants found:

• chr1-149923867-CG-C
• chr1-149923867-CG-CGG

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Strong PM2

The NM_005850.5(SF3B4):​c.1060delC​(p.Arg354GlufsTer26) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000207 in 1,449,530 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SF3B4 NM_005850.5 frameshift
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.767
• Publications: 0 publications found

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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 10 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

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.1060delC	p.Arg354GlufsTer26	frameshift	Exon 5 of 6	NP_005841.1	Q15427

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SF3B4	ENST00000271628.9	TSL:1 MANE Select	c.1060delC	p.Arg354GlufsTer26	frameshift	Exon 5 of 6	ENSP00000271628.8	Q15427
	SF3B4	ENST00000940764.1		c.751delC	p.Arg251GlufsTer26	frameshift	Exon 5 of 6	ENSP00000610823.1
	SF3B4	ENST00000940765.1		c.589delC	p.Arg197GlufsTer26	frameshift	Exon 5 of 6	ENSP00000610824.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000207 AC: 3 AN: 1449530 Hom.: 0 Cov.: 32 AF XY: 0.00000277 AC XY: 2 AN XY: 721394

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32476

American (AMR) AF: 0.0000241 AC: 1 AN: 41412

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25630

East Asian (EAS) AF: 0.00 AC: 0 AN: 38906

South Asian (SAS) AF: 0.00 AC: 0 AN: 84760

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53090

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5532

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1108008

Other (OTH) AF: 0.00 AC: 0 AN: 59716

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0482410), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.77

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: rs782357237; hg19: chr1-149895759; COSMIC: COSV54966169; COSMIC: COSV54966169;