Genetic Variant NM_004630.4:c.1429A>G (chr11-64767053-T-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004630.4(SF1):c.1429A>G(p.Met477Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000707 in 1,414,522 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/18 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. M477L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

SF1
NM_004630.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.08

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.10913357).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SF1	NM_004630.4	MANE Select	c.1429A>G	p.Met477Val	missense	Exon 12 of 13	NP_004621.2
SF1	NM_001378957.1		c.1804A>G	p.Met602Val	missense	Exon 12 of 13	NP_001365886.1	A0A7P0T9U7
SF1	NM_001378956.1		c.1804A>G	p.Met602Val	missense	Exon 12 of 14	NP_001365885.1	A0A9L9PXE4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SF1	ENST00000377390.8	TSL:1 MANE Select	c.1429A>G	p.Met477Val	missense	Exon 12 of 13	ENSP00000366607.3	Q15637-1
SF1	ENST00000377387.5	TSL:1	c.1804A>G	p.Met602Val	missense	Exon 12 of 13	ENSP00000366604.1	Q15637-5
SF1	ENST00000334944.9	TSL:1	c.1429A>G	p.Met477Val	missense	Exon 12 of 14	ENSP00000334414.5	Q15637-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.07e-7

AC:

AN:

1414522

Hom.:

Cov.:

AF XY:

0.00000143

AC XY:

AN XY:

698548

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31908

American (AMR)

AF:

0.00

AC:

AN:

38592

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23616

East Asian (EAS)

AF:

0.00

AC:

AN:

38838

South Asian (SAS)

AF:

0.00

AC:

AN:

80324

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5556

European-Non Finnish (NFE)

AF:

9.21e-7

AC:

AN:

1085840

Other (OTH)

AF:

0.00

AC:

AN:

58224

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.098

BayesDel_addAF

Uncertain

0.031

BayesDel_noAF

Benign

-0.19

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.011

Eigen

Benign

-0.17

Eigen_PC

Benign

0.0030

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.47

M_CAP

Benign

0.025

MetaRNN

Benign

0.11

MetaSVM

Benign

-1.0

PhyloP100

2.1

PROVEAN

Benign

-0.81

REVEL

Benign

0.042

Sift

Pathogenic

0.0

Sift4G

Benign

0.34

Polyphen

0.17

Vest4

0.40

MutPred

0.26

Gain of MoRF binding (P = 0.0074)

MVP

0.30

ClinPred

0.47

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.9

Varity_R

0.67

Mutation Taster

=78/22

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over