11-64778122-A-C

Position:

• chr11-64778122-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001378957.1(SF1):​c.271T>G​(p.Ser91Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000462 in 648,730 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000046 (0 hom.)
• Consequence: SF1 NM_001378957.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0850

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09465709).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SF1	NM_004630.4	c.31+240T>G		intron_variant		ENST00000377390.8	NP_004621.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SF1	ENST00000377390.8	c.31+240T>G		intron_variant		1	NM_004630.4	ENSP00000366607.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000462 AC: 3 AN: 648730 Hom.: 0 Cov.: 9 AF XY: 0.00000651 AC XY: 2 AN XY: 307128

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: 0.00000346

Gnomad4 OTH exome AF: 0.0000440

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 07, 2023

The c.271T>G (p.S91A) alteration is located in exon 1 (coding exon 1) of the SF1 gene. This alteration results from a T to G substitution at nucleotide position 271, causing the serine (S) at amino acid position 91 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	15
DANN	Benign	0.87
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.15	T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.095	T
MetaSVM	Benign	-1.1	T
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-0.34	N
REVEL	Benign	0.025
Sift	Uncertain	0.011	D
Sift4G	Benign	0.42	T
Polyphen		0.0060	B
Vest4		0.13
MutPred		0.33		Loss of phosphorylation at S91 (P = 4e-04);
MVP		0.45
MPC		1.4
ClinPred		0.066	T
GERP RS		1.2
gMVP		0.035

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: rs1939682730; hg19: chr11-64545594;