1-149923669-T-TG

Variant names:

• chr1-149923669-T-TG
• rs387907186
• NM_005850.5:c.1147dupC

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PVS1_Strong PP5

The NM_005850.5(SF3B4):​c.1147dupC​(p.His383ProfsTer103) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000146 in 1,374,550 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: SF3B4 NM_005850.5 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:2
• Conservation: PhyloP100: 7.85
• Publications: 6 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: Uncertain_significance. The variant received 5 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 10 pathogenic variants in the truncated region.
• PP5: Variant 1-149923669-T-TG is Pathogenic according to our data. Variant chr1-149923669-T-TG is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 31651.

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.1147dupC	p.His383ProfsTer103	frameshift	Exon 6 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.1147dupC	p.His383ProfsTer103	frameshift	Exon 6 of 6	ENSP00000271628.8	Q15427
	SF3B4	ENST00000940764.1		c.838dupC	p.His280ProfsTer103	frameshift	Exon 6 of 6	ENSP00000610823.1
	SF3B4	ENST00000940765.1		c.676dupC	p.His226ProfsTer103	frameshift	Exon 6 of 6	ENSP00000610824.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000981 AC: 16 AN: 163016 AF XY: 0.0000330

Gnomad AFR exome AF: 0.000187

Gnomad AMR exome AF: 0.0000695

Gnomad ASJ exome AF: 0.000182

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000537

Gnomad NFE exome AF: 0.000121

Gnomad OTH exome AF: 0.000292

GnomAD4 exome AF: 0.0000146 AC: 20 AN: 1374550 Hom.: 0 Cov.: 32 AF XY: 0.0000117 AC XY: 8 AN XY: 681464

⚠️ 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: 27508

American (AMR) AF: 0.0000411 AC: 1 AN: 24304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22236

East Asian (EAS) AF: 0.00 AC: 0 AN: 34130

South Asian (SAS) AF: 0.0000139 AC: 1 AN: 71878

European-Finnish (FIN) AF: 0.000289 AC: 15 AN: 51978

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5466

European-Non Finnish (NFE) AF: 0.00000185 AC: 2 AN: 1080466

Other (OTH) AF: 0.0000177 AC: 1 AN: 56584

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
2	-	-	Nager syndrome (2)
1	-	-	Inborn genetic diseases (1)
-	1	-	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.9
Mutation Taster		=1/199	disease causing (ClinVar)

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: rs387907186; hg19: chr1-149895561; COSMIC: COSV54965474; COSMIC: COSV54965474;