Genetic Variant SF1:p.Pro130Gln (chr11-64778004-G-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The ENST00000377387.5(SF1):c.389C>A(p.Pro130Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P130L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SF1
ENST00000377387.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.277

Publications

0 publications found

Variant links:

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]

SF1 links:

SF1-DT (HGNC:55278): (SF1 divergent transcript)

SF1-DT links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0578897).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SF1	NM_004630.4 link	c.31+358C>A		intron_variant	Intron 1 of 12	ENST00000377390.8	NP_004621.2	Q15637-1A0A024R572

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SF1	ENST00000377390.8 link	c.31+358C>A		intron_variant	Intron 1 of 12	1	NM_004630.4	ENSP00000366607.3		Q15637-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

852288

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

395682

African (AFR)

AF:

0.00

AC:

AN:

16084

American (AMR)

AF:

0.00

AC:

AN:

1642

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

5614

East Asian (EAS)

AF:

0.00

AC:

AN:

4372

South Asian (SAS)

AF:

0.00

AC:

AN:

17478

European-Finnish (FIN)

AF:

0.00

AC:

AN:

2180

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1718

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

774750

Other (OTH)

AF:

0.00

AC:

AN:

28450

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.60

CADD

Benign

(source)

DANN

Benign

0.95

Eigen

Benign

-0.94

Eigen_PC

Benign

-0.98

FATHMM_MKL

Benign

0.052

LIST_S2

Benign

0.30

M_CAP

Uncertain

0.27

MetaRNN

Benign

0.058

MetaSVM

Benign

-0.99

PhyloP100

-0.28

PrimateAI

Uncertain

0.78

PROVEAN

Benign

0.73

REVEL

Benign

0.053

Sift

Benign

0.14

Sift4G

Benign

0.56

Polyphen

0.0

Vest4

0.15

MutPred

0.15

Loss of catalytic residue at P130 (P = 0.0307);

MVP

0.17

MPC

1.5

ClinPred

0.27

GERP RS

-0.59

PromoterAI

0.074

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

gMVP

0.074

Mutation Taster

=92/8

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over