rs574177694

Variant names:

• chr11-64766916-G-A
• rs574177694
• ENST00000377394.7:c.1570C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Moderate BP6_Moderate BS2

The NM_001440580.1(SF1):​c.1945C>T​(p.Leu649Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000488 in 1,229,426 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0000071 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000046 (0 hom.)
• Consequence: SF1 NM_001440580.1 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.04
• Publications: 1 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.108328015).
• BP6: Variant 11-64766916-G-A is Benign according to our data. Variant chr11-64766916-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 3317811.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001440580.1. 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.1566C>T	p.Pro522Pro	synonymous	Exon 12 of 13	NP_004621.2
	SF1	NM_001440580.1		c.1945C>T	p.Leu649Phe	missense	Exon 12 of 13	NP_001427509.1
	SF1	NM_001440581.1		c.1936C>T	p.Leu646Phe	missense	Exon 12 of 13	NP_001427510.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SF1	ENST00000377394.7	TSL:1	c.1570C>T	p.Leu524Phe	missense	Exon 12 of 13	ENSP00000366611.3	Q15637-6
	SF1	ENST00000377390.8	TSL:1 MANE Select	c.1566C>T	p.Pro522Pro	synonymous	Exon 12 of 13	ENSP00000366607.3	Q15637-1
	SF1	ENST00000377387.5	TSL:1	c.1941C>T	p.Pro647Pro	synonymous	Exon 12 of 13	ENSP00000366604.1	Q15637-5

Frequencies

GnomAD3 genomes AF: 0.00000706 AC: 1 AN: 141720 Hom.: 0 Cov.: 31

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: 0.000242

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000140 AC: 2 AN: 142530 AF XY: 0.0000130

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: 0.00000460 AC: 5 AN: 1087608 Hom.: 0 Cov.: 35 AF XY: 0.00000573 AC XY: 3 AN XY: 523834

African (AFR) AF: 0.00 AC: 0 AN: 22472

American (AMR) AF: 0.00 AC: 0 AN: 17688

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10676

East Asian (EAS) AF: 0.00 AC: 0 AN: 17470

South Asian (SAS) AF: 0.0000205 AC: 1 AN: 48734

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31136

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3712

European-Non Finnish (NFE) AF: 0.00000446 AC: 4 AN: 896258

Other (OTH) AF: 0.00 AC: 0 AN: 39462

GnomAD4 genome AF: 0.00000705 AC: 1 AN: 141818 Hom.: 0 Cov.: 31 AF XY: 0.0000146 AC XY: 1 AN XY: 68560

African (AFR) AF: 0.00 AC: 0 AN: 38506

American (AMR) AF: 0.00 AC: 0 AN: 13704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3414

East Asian (EAS) AF: 0.00 AC: 0 AN: 4316

South Asian (SAS) AF: 0.000241 AC: 1 AN: 4144

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8940

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 272

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 65694

Other (OTH) AF: 0.00 AC: 0 AN: 1948

ExAC AF: 0.0000171 AC: 2

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

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	0.14
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.13
CADD	Benign	9.1
DANN	Uncertain	1.0
DEOGEN2	Benign	0.015	T
Eigen	Benign	0.091
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.46	T
M_CAP	Benign	0.061	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.75	T
PhyloP100		1.0
PROVEAN	Benign	-0.31	N
REVEL	Benign	0.15
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.33	T
Polyphen		0.0	B
Vest4		0.30
MutPred		0.12		Gain of methylation at K529 (P = 0.0678)
MVP		0.56
ClinPred		0.13	T
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=90/10	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: rs574177694; hg19: chr11-64534388;