1-149923669-TG-TGG

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: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SF3B4	NM_005850.5	c.1147dupC	p.His383ProfsTer103	frameshift_variant	Exon 6 of 6	ENST00000271628.9	NP_005841.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SF3B4	ENST00000271628.9	c.1147dupC	p.His383ProfsTer103	frameshift_variant	Exon 6 of 6	1	NM_005850.5	ENSP00000271628.8

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

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Nager syndrome Pathogenic:2

Sep 07, 2012

Clinical Genetics Research Group, University of Calgary

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

May 04, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Inborn genetic diseases Pathogenic:1

Oct 06, 2014

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

May 04, 2022

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Uncertain:1

Dec 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change results in a frameshift in the SF3B4 gene (p.His383Profs*103). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 42 amino acid(s) of the SF3B4 protein and extend the protein by 60 additional amino acid residues. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This frameshift has been observed in individual(s) with SF3B4-related conditions (PMID: 22541558). ClinVar contains an entry for this variant (Variation ID: 31651). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Computational scores

Source: dbNSFP v4.3

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;