chr11-64768129-G-A

Variant names:

• chr11-64768129-G-A
• rs200685412
• NM_004630.4:c.1045C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_004630.4(SF1):​c.1045C>T​(p.Pro349Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000372 in 1,612,072 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: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000040 (0 hom.)
• Consequence: SF1 NM_004630.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.29
• Publications: 2 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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.13259694).
• BS2: High AC in GnomAdExome4 at 58 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.1045C>T	p.Pro349Ser	missense	Exon 9 of 13	NP_004621.2
	SF1	NM_001378957.1		c.1420C>T	p.Pro474Ser	missense	Exon 9 of 13	NP_001365886.1	A0A7P0T9U7
	SF1	NM_001378956.1		c.1420C>T	p.Pro474Ser	missense	Exon 9 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.1045C>T	p.Pro349Ser	missense	Exon 9 of 13	ENSP00000366607.3	Q15637-1
	SF1	ENST00000377387.5	TSL:1	c.1420C>T	p.Pro474Ser	missense	Exon 9 of 13	ENSP00000366604.1	Q15637-5
	SF1	ENST00000334944.9	TSL:1	c.1045C>T	p.Pro349Ser	missense	Exon 9 of 14	ENSP00000334414.5	Q15637-2

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152244 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000483 AC: 12 AN: 248556 AF XY: 0.0000743

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.0000397 AC: 58 AN: 1459828 Hom.: 0 Cov.: 32 AF XY: 0.0000496 AC XY: 36 AN XY: 726092

African (AFR) AF: 0.00 AC: 0 AN: 33396

American (AMR) AF: 0.00 AC: 0 AN: 44340

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26060

East Asian (EAS) AF: 0.00 AC: 0 AN: 39638

South Asian (SAS) AF: 0.000651 AC: 56 AN: 86078

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53268

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111004

Other (OTH) AF: 0.0000332 AC: 2 AN: 60292

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152244 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74368

African (AFR) AF: 0.00 AC: 0 AN: 41458

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68042

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000330 AC: 4

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	Benign	0.064
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.39
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.24	T
Eigen	Benign	0.092
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.0039	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.81	L
PhyloP100		4.3
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.13
Sift	Benign	0.033	D
Sift4G	Benign	0.17	T
Polyphen		0.40	B
Vest4		0.25
MutPred		0.26		Gain of phosphorylation at P349 (P = 0.021)
MVP		0.39
MPC		0.57
ClinPred		0.17	T
GERP RS		5.4
PromoterAI		0.14	Neutral
Varity_R		0.43
gMVP		0.46
Mutation Taster		=80/20	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: rs200685412; hg19: chr11-64535601;