ENST00000377394.7:c.1420A>G

Variant names:

• chr11-64767066-T-C
• rs147412519
• ENST00000377394.7:c.1420A>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The ENST00000377394.7(SF1):​c.1420A>G​(p.Thr474Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000282 in 1,583,544 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 0.00023 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00029 (0 hom.)
• Consequence: SF1 ENST00000377394.7 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.264
• Publications: 5 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.028053313).
• BP6: Variant 11-64767066-T-C is Benign according to our data. Variant chr11-64767066-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 3160783.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 35 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000377394.7. 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.1416A>G	p.Pro472Pro	synonymous	Exon 12 of 13	NP_004621.2
	SF1	NM_001440580.1		c.1795A>G	p.Thr599Ala	missense	Exon 12 of 13	NP_001427509.1
	SF1	NM_001440581.1		c.1786A>G	p.Thr596Ala	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.1420A>G	p.Thr474Ala	missense	Exon 12 of 13	ENSP00000366611.3	Q15637-6
	SF1	ENST00000377390.8	TSL:1 MANE Select	c.1416A>G	p.Pro472Pro	synonymous	Exon 12 of 13	ENSP00000366607.3	Q15637-1
	SF1	ENST00000377387.5	TSL:1	c.1791A>G	p.Pro597Pro	synonymous	Exon 12 of 13	ENSP00000366604.1	Q15637-5

Frequencies

GnomAD3 genomes AF: 0.000230 AC: 35 AN: 151894 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000378 AC: 87 AN: 230266 AF XY: 0.000354

Gnomad AFR exome AF: 0.000189

Gnomad AMR exome AF: 0.0000318

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000197

Gnomad NFE exome AF: 0.000674

Gnomad OTH exome AF: 0.000547

GnomAD4 exome AF: 0.000287 AC: 411 AN: 1431534 Hom.: 0 Cov.: 35 AF XY: 0.000277 AC XY: 196 AN XY: 708604

African (AFR) AF: 0.00 AC: 0 AN: 32602

American (AMR) AF: 0.0000240 AC: 1 AN: 41700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24444

East Asian (EAS) AF: 0.00 AC: 0 AN: 39130

South Asian (SAS) AF: 0.000242 AC: 20 AN: 82692

European-Finnish (FIN) AF: 0.000365 AC: 19 AN: 52100

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5612

European-Non Finnish (NFE) AF: 0.000321 AC: 351 AN: 1094300

Other (OTH) AF: 0.000339 AC: 20 AN: 58954

GnomAD4 genome AF: 0.000230 AC: 35 AN: 152010 Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16 AN XY: 74300

African (AFR) AF: 0.000145 AC: 6 AN: 41424

American (AMR) AF: 0.00 AC: 0 AN: 15272

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5134

South Asian (SAS) AF: 0.000416 AC: 2 AN: 4812

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000382 AC: 26 AN: 67976

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000349 Hom.: 0

Bravo AF: 0.000230

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000511 AC: 62

ClinVar

ClinVar submissions

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	0.060
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	6.3
DANN	Benign	0.40
DEOGEN2	Benign	0.0046	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.25	T
M_CAP	Benign	0.0053	T
MetaRNN	Benign	0.028	T
MetaSVM	Benign	-0.95	T
PhyloP100		-0.26
PROVEAN	Benign	-0.40	N
REVEL	Benign	0.093
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.79	T
Polyphen		0.0	B
Vest4		0.28
MVP		0.26
ClinPred		0.015	T
GERP RS		-2.5
Mutation Taster		=94/6	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: rs147412519; hg19: chr11-64534538;