chr11-64767577-G-A

Variant names:

• chr11-64767577-G-A
• rs931843023
• NM_004630.4:c.1336C>T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_004630.4(SF1):​c.1336C>T​(p.Pro446Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000569 in 1,404,858 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000057 (0 hom.)
• Consequence: SF1 NM_004630.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.38

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

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.2784434).
• BS2: High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SF1	NM_004630.4	c.1336C>T	p.Pro446Ser	missense_variant	Exon 10 of 13	ENST00000377390.8	NP_004621.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SF1	ENST00000377390.8	c.1336C>T	p.Pro446Ser	missense_variant	Exon 10 of 13	1	NM_004630.4	ENSP00000366607.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000569 AC: 8 AN: 1404858 Hom.: 0 Cov.: 33 AF XY: 0.00000576 AC XY: 4 AN XY: 694824

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: 0.00000736

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Uncertain	0.013	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	.;T;.;.;.;T;.;T
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;T;D;D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.28	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	1.2	.;L;L;L;L;.;.;.
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.4	N;N;N;N;N;D;N;D
REVEL	Benign	0.097
Sift	Uncertain	0.010	D;.;D;D;D;D;D;D
Sift4G	Benign	0.16	T;T;T;D;T;T;T;.
Polyphen		0.84	P;P;B;B;B;.;.;.
Vest4		0.51
MutPred		0.18		.;Gain of phosphorylation at P446 (P = 0.0444);Gain of phosphorylation at P446 (P = 0.0444);Gain of phosphorylation at P446 (P = 0.0444);Gain of phosphorylation at P446 (P = 0.0444);.;.;.;
MVP		0.43
MPC		0.68
ClinPred		0.91	D
GERP RS		5.8
Varity_R		0.25
gMVP		0.25

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: rs931843023; hg19: chr11-64535049;