22-30342286-T-C

Variant names:

• chr22-30342286-T-C
• rs763646092
• NM_005877.6:c.791A>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005877.6(SF3A1):​c.791A>G​(p.Lys264Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,866 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 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: 0.0000014 (0 hom.)
• Consequence: SF3A1 NM_005877.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.97

Genes affected

SF3A1 (HGNC:10765): (splicing factor 3a subunit 1) This gene encodes a subunit of the splicing factor 3a protein complex. The splicing factor 3a heterotrimer is a component of the mature U2 small nuclear ribonucleoprotein particle (snRNP). U2 small nuclear ribonucleoproteins play a critical role in spliceosome assembly and pre-mRNA splicing. [provided by RefSeq, Aug 2014]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08746433).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SF3A1	NM_005877.6	c.791A>G	p.Lys264Arg	missense_variant	Exon 6 of 16	ENST00000215793.13	NP_005868.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SF3A1	ENST00000215793.13	c.791A>G	p.Lys264Arg	missense_variant	Exon 6 of 16	1	NM_005877.6	ENSP00000215793.7
SF3A1	ENST00000411423.1	n.64-3107A>G		intron_variant	Intron 1 of 3	4		ENSP00000412715.1
SF3A1	ENST00000447376.1	n.*133A>G		downstream_gene_variant		5		ENSP00000397267.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000402 AC: 1 AN: 248512 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134562

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461866 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 727232

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 07, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.791A>G (p.K264R) alteration is located in exon 6 (coding exon 6) of the SF3A1 gene. This alteration results from a A to G substitution at nucleotide position 791, causing the lysine (K) at amino acid position 264 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.079	T
Eigen	Benign	-0.21
Eigen_PC	Benign	0.074
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.0038	T
MetaRNN	Benign	0.087	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.1	N
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-0.10	N
REVEL	Benign	0.062
Sift	Benign	0.81	T
Sift4G	Benign	0.75	T
Polyphen		0.0020	B
Vest4		0.20
MutPred		0.35		Loss of ubiquitination at K264 (P = 0.0071);
MVP		0.25
MPC		0.69
ClinPred		0.36	T
GERP RS		6.1
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.8
Varity_R		0.15
gMVP		0.13

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: rs763646092; hg19: chr22-30738275;