chr1-149923669-T-TG

Position:

• chr1-149923669-T-TG

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 5P and 4B. PVS1_Strong PP5 BS2

The NM_005850.5(SF3B4):​c.1147_1148insC​(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. 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:1
• Conservation: PhyloP100: 7.85

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 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 4 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 id is 31651.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=1}.
• BS2: High AC in GnomAdExome4 at 20 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SF3B4	NM_005850.5	c.1147_1148insC	p.His383ProfsTer103	frameshift_variant	6/6	ENST00000271628.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SF3B4	ENST00000271628.9	c.1147_1148insC	p.His383ProfsTer103	frameshift_variant	6/6	1	NM_005850.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000411

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000139

Gnomad4 FIN exome AF: 0.000289

Gnomad4 NFE exome AF: 0.00000185

Gnomad4 OTH exome AF: 0.0000177

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Nager syndrome Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	May 04, 2012	- -
Pathogenic, no assertion criteria provided	research	Clinical Genetics Research Group, University of Calgary	Sep 07, 2012	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 06, 2014

The c.1147dupC (p.H383Pfs*103) alteration, located in coding exon 6 of the SF3B4 gene, consists of a duplication of C at position 1147, causing a translational frameshift with a predicted alternate stop codon after 103 amino acids. Frameshift alterations are typically deleterious in nature (Richards, 2015). The alteration is not observed in healthy cohorts: Based on data from the NHLBI Exome Sequencing Project (ESP), the SF3B4 c.1147DUPC alteration was not observed among 6,476 individuals tested. Allele frequency data for this nucleotide position are not currently available from the 1000 Genomes Project and the alteration is not currently listed in the Database of Single Nucleotide Polymorphisms (dbSNP). The alteration has been observed in affected individuals: This alteration was previously reported in a one year old male and his 28 year old mother. Both individuals had dwonslanted palperbral fissures, micrognathia, abnormal soft palate, abnormal ears, and hearing loss. The son was absent his right thumb and had a small left thumb. The mother had small thumbs and bilateral radioulnar synostosis (Bernier 2012). Based on the available evidence, this alteration is classified as pathogenic. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs387907186; hg19: chr1-149895561;