1-149923867-CG-CGG

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_Strong

The NM_005850.5(SF3B4):​c.1060dupC​(p.Arg354ProfsTer132) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000159 in 1,449,332 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: 0.000016 (0 hom.)
• Consequence: SF3B4 NM_005850.5 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 B:1
• Conservation: PhyloP100: 0.767
• Publications: 13 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 4 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SF3B4	NM_005850.5	c.1060dupC	p.Arg354ProfsTer132	frameshift_variant	Exon 5 of 6	ENST00000271628.9	NP_005841.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SF3B4	ENST00000271628.9	c.1060dupC	p.Arg354ProfsTer132	frameshift_variant	Exon 5 of 6	1	NM_005850.5	ENSP00000271628.8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.000141 AC: 32 AN: 226982 AF XY: 0.0000805

Gnomad AFR exome AF: 0.000141

Gnomad AMR exome AF: 0.000300

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000620

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000163

Gnomad OTH exome AF: 0.000185

GnomAD4 exome AF: 0.0000159 AC: 23 AN: 1449332 Hom.: 0 Cov.: 32 AF XY: 0.0000153 AC XY: 11 AN XY: 721278

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

African (AFR) AF: 0.0000616 AC: 2 AN: 32478

American (AMR) AF: 0.000193 AC: 8 AN: 41384

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25618

East Asian (EAS) AF: 0.00 AC: 0 AN: 38904

South Asian (SAS) AF: 0.0000118 AC: 1 AN: 84742

European-Finnish (FIN) AF: 0.0000566 AC: 3 AN: 53022

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5534

European-Non Finnish (NFE) AF: 0.00000722 AC: 8 AN: 1107938

Other (OTH) AF: 0.0000167 AC: 1 AN: 59712

⚠️ 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:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Nager syndrome Pathogenic:1

Sep 07, 2012

Clinical Genetics Research Group, University of Calgary

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

not provided Pathogenic:1

Aug 03, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ClinVar contains an entry for this variant (Variation ID: 208831). This frameshift has been observed in individual(s) with Nager syndrome (PMID: 22541558, 24003905, 27622494). In at least one individual the variant was observed to be de novo. 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 sequence change results in a frameshift in the SF3B4 gene (p.Arg354Profs*132). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 71 amino acid(s) of the SF3B4 protein and extend the protein by 60 additional amino acid residues. For these reasons, this variant has been classified as Pathogenic. -

not specified Benign:1

May 04, 2022

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.77
Mutation Taster		=2/198	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: rs782357237; hg19: chr1-149895759; COSMIC: COSV54964642; COSMIC: COSV54964642;