chr11-64769083-T-C

Variant names:

• chr11-64769083-T-C
• rs780745897
• NM_004630.4:c.826A>G

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4 BS2

The NM_004630.4(SF1):​c.826A>G​(p.Thr276Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,872 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: SF1 NM_004630.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.63
• Publications: 0 publications found

Genes affected

SF1 (HGNC:12950): (splicing factor 1) This gene encodes a nuclear pre-mRNA splicing factor. The encoded protein specifically recognizes the intron branch point sequence at the 3' splice site, together with the large subunit of U2 auxiliary factor (U2AF), and is required for the early stages of spliceosome assembly. It also plays a role in nuclear pre-mRNA retention and transcriptional repression. The encoded protein contains an N-terminal U2AF ligand motif, a central hnRNP K homology motif and quaking 2 region which bind a key branch-site adenosine within the branch point sequence, a zinc knuckles domain, and a C-terminal proline-rich domain. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2016]

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3711355).
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004630.4. 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
	SF1	NM_004630.4	MANE Select	c.826A>G	p.Thr276Ala	missense	Exon 8 of 13	NP_004621.2
	SF1	NM_001378957.1		c.1201A>G	p.Thr401Ala	missense	Exon 8 of 13	NP_001365886.1	A0A7P0T9U7
	SF1	NM_001378956.1		c.1201A>G	p.Thr401Ala	missense	Exon 8 of 14	NP_001365885.1	A0A9L9PXE4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SF1	ENST00000377390.8	TSL:1 MANE Select	c.826A>G	p.Thr276Ala	missense	Exon 8 of 13	ENSP00000366607.3	Q15637-1
	SF1	ENST00000377387.5	TSL:1	c.1201A>G	p.Thr401Ala	missense	Exon 8 of 13	ENSP00000366604.1	Q15637-5
	SF1	ENST00000334944.9	TSL:1	c.826A>G	p.Thr276Ala	missense	Exon 8 of 14	ENSP00000334414.5	Q15637-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000159 AC: 4 AN: 251496 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 0.00000342 AC: 5 AN: 1461872 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727240

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000894 AC: 4 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111994

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Benign	0.0051	T
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.075	D
MetaRNN	Benign	0.37	T
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Benign	1.4	L
PhyloP100		7.6
PrimateAI	Uncertain	0.79	T
PROVEAN	Uncertain	-2.5	D
REVEL	Uncertain	0.48
Sift	Benign	0.048	D
Sift4G	Benign	0.092	T
Polyphen		0.81	P
Vest4		0.51
MutPred		0.28		Loss of sheet (P = 0.0126)
MVP		0.83
MPC		2.2
ClinPred		0.50	T
GERP RS		5.8
PromoterAI		0.0067	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.59
gMVP		0.92
Mutation Taster		=34/66	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs780745897; hg19: chr11-64536555;