chr1-149923582-A-G

Position:

• chr1-149923582-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_005850.5(SF3B4):​c.1235T>C​(p.Val412Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000213 in 1,408,692 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SF3B4 NM_005850.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.15

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.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SF3B4. . Gene score misZ 3.8666 (greater than the threshold 3.09). Trascript score misZ 4.1827 (greater than threshold 3.09). GenCC has associacion of gene with Nager acrofacial dysostosis, SF3B4-related acrofacial dysostosis, acrofacial dysostosis Rodriguez type.
• BP4: Computational evidence support a benign effect (MetaRNN=0.08058822).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SF3B4	NM_005850.5	c.1235T>C	p.Val412Ala	missense_variant	6/6	ENST00000271628.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SF3B4	ENST00000271628.9	c.1235T>C	p.Val412Ala	missense_variant	6/6	1	NM_005850.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000213 AC: 3 AN: 1408692 Hom.: 0 Cov.: 32 AF XY: 0.00000143 AC XY: 1 AN XY: 700340

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000274

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Nager syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Molecular Genetics, Royal Melbourne Hospital

Nov 03, 2022

This sequence change in SF3B4 is predicted to replace valine with alanine at codon 412, p.(Val412Ala). The valine residue is moderately conserved (100 vertebrates, UCSC), and is not located in an annotated domain. There is a moderate physicochemical difference between valine and alanine. SF3B4 is highly intolerant to missense variation, however no pathogenic missense have been reported (gnomAD v2.1; ClinVar). This variant is absent from the population database gnomAD v2.1 and v3.1. To our knowledge, this variant has not been reported in the relevant literature or databases. Multiple lines of computational evidence have conflicting predictions for the missense substitution (5/6 algorithms predict benign). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: PM2_Supporting, PP2. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	22
DANN	Benign	0.58
DEOGEN2	Benign	0.024	T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.049
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.62	T
M_CAP	Benign	0.0066	T
MetaRNN	Benign	0.081	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.90	L
MutationTaster	Benign	0.99	D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	0.14	N
REVEL	Benign	0.087
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.47	T
Polyphen		0.0080	B
Vest4		0.18
MutPred		0.23		Gain of glycosylation at P413 (P = 0.0941);
MVP		0.37
MPC		0.69
ClinPred		0.29	T
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.087
gMVP		0.028

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-149895474;