chr19-2248161-A-G

Variant names:

• chr19-2248161-A-G
• rs2024961423
• NM_007165.5:c.1010A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_007165.5(SF3A2):​c.1010A>G​(p.His337Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000767 in 1,303,904 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H337L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 7.7e-7 (0 hom.)
• Consequence: SF3A2 NM_007165.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.344
• Publications: 0 publications found

Genes affected

SF3A2 (HGNC:10766): (splicing factor 3a subunit 2) This gene encodes subunit 2 of the splicing factor 3a protein complex. The splicing factor 3a heterotrimer includes subunits 1, 2 and 3 and is necessary for the in vitro conversion of 15S U2 snRNP into an active 17S particle that performs pre-mRNA splicing. Subunit 2 interacts with subunit 1 through its amino-terminus while the single zinc finger domain of subunit 2 plays a role in its binding to the 15S U2 snRNP. Subunit 2 may also function independently of its RNA splicing function as a microtubule-binding protein. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09085509).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007165.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SF3A2	NM_007165.5	MANE Select	c.1010A>G	p.His337Arg	missense	Exon 9 of 9	NP_009096.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SF3A2	ENST00000221494.10	TSL:1 MANE Select	c.1010A>G	p.His337Arg	missense	Exon 9 of 9	ENSP00000221494.3	Q15428
	SF3A2	ENST00000866932.1		c.1112A>G	p.His371Arg	missense	Exon 9 of 9	ENSP00000536991.1
	SF3A2	ENST00000866930.1		c.1010A>G	p.His337Arg	missense	Exon 10 of 10	ENSP00000536989.1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome AF: 7.67e-7 AC: 1 AN: 1303904 Hom.: 0 Cov.: 26 AF XY: 0.00000155 AC XY: 1 AN XY: 646812

⚠️ 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: 29092

American (AMR) AF: 0.00 AC: 0 AN: 34486

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22234

East Asian (EAS) AF: 0.00 AC: 0 AN: 34656

South Asian (SAS) AF: 0.00 AC: 0 AN: 74678

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41576

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3768

European-Non Finnish (NFE) AF: 9.91e-7 AC: 1 AN: 1009328

Other (OTH) AF: 0.00 AC: 0 AN: 54086

⚠️ 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.: 29

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	19
DANN	Benign	0.63
DEOGEN2	Benign	0.060	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.059	N
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.064	D
MetaRNN	Benign	0.091	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.34
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-0.040	N
REVEL	Benign	0.056
Sift	Benign	0.31	T
Sift4G	Benign	0.56	T
Polyphen		0.0010	B
Vest4		0.23
MutPred		0.30		Gain of methylation at H337 (P = 0.0323)
MVP		0.33
MPC		0.77
ClinPred		0.22	T
GERP RS		3.9
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.1
Varity_R		0.11
gMVP		0.10
Mutation Taster		=99/1	polymorphism

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: rs2024961423; hg19: chr19-2248160;