chr1-37976886-C-G

Variant names:

• chr1-37976886-C-G
• rs1475746388
• NM_006802.4:c.1003G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_006802.4(SF3A3):​c.1003G>C​(p.Gly335Arg) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SF3A3 NM_006802.4 missense, splice_region
• Scores: Splicing: ADA: 0.9572
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.28
• Publications: 0 publications found

Genes affected

SF3A3 (HGNC:10767): (splicing factor 3a subunit 3) This gene encodes subunit 3 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 3 interacts with subunit 1 through its amino-terminus while the zinc finger domain of subunit 3 plays a role in its binding to the 15S U2 snRNP. This gene has a pseudogene on chromosome 20. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2016]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006802.4. 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
	SF3A3	NM_006802.4	MANE Select	c.1003G>C	p.Gly335Arg	missense splice_region	Exon 12 of 17	NP_006793.1	Q12874
	SF3A3	NM_001320830.2		c.844G>C	p.Gly282Arg	missense splice_region	Exon 10 of 15	NP_001307759.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SF3A3	ENST00000373019.5	TSL:1 MANE Select	c.1003G>C	p.Gly335Arg	missense splice_region	Exon 12 of 17	ENSP00000362110.4	Q12874
	SF3A3	ENST00000896916.1		c.1003G>C	p.Gly335Arg	missense splice_region	Exon 12 of 18	ENSP00000566975.1
	SF3A3	ENST00000963486.1		c.1057G>C	p.Gly353Arg	missense splice_region	Exon 13 of 18	ENSP00000633545.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.018	T
MetaRNN	Uncertain	0.67	D
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.1	L
PhyloP100		7.3
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.30
Sift	Benign	0.26	T
Sift4G	Benign	0.48	T
Polyphen		0.96	D
Vest4		0.73
MutPred		0.30		Gain of MoRF binding (P = 0.0199)
MVP		0.54
MPC		2.1
ClinPred		0.93	D
GERP RS		5.7
Varity_R		0.35
gMVP		0.78
Mutation Taster		=23/77	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.96
dbscSNV1_RF	Pathogenic	0.77
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: rs1475746388; hg19: chr1-38442558;