rs139117230

Variant names:

• chr11-64767798-C-A
• rs139117230
• NM_004630.4:c.1115G>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_004630.4(SF1):​c.1115G>T​(p.Gly372Val) variant causes a missense change. The variant allele was found at a frequency of 0.000332 in 1,613,690 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00035 (0 hom.)
• Consequence: SF1 NM_004630.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.86
• 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: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAd4 at 30 AD gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SF1	NM_004630.4	MANE Select	c.1115G>T	p.Gly372Val	missense	Exon 10 of 13	NP_004621.2
	SF1	NM_001378957.1		c.1490G>T	p.Gly497Val	missense	Exon 10 of 13	NP_001365886.1	A0A7P0T9U7
	SF1	NM_001378956.1		c.1490G>T	p.Gly497Val	missense	Exon 10 of 14	NP_001365885.1	A0A9L9PXE4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SF1	ENST00000377390.8	TSL:1 MANE Select	c.1115G>T	p.Gly372Val	missense	Exon 10 of 13	ENSP00000366607.3	Q15637-1
	SF1	ENST00000377387.5	TSL:1	c.1490G>T	p.Gly497Val	missense	Exon 10 of 13	ENSP00000366604.1	Q15637-5
	SF1	ENST00000334944.9	TSL:1	c.1115G>T	p.Gly372Val	missense	Exon 10 of 14	ENSP00000334414.5	Q15637-2

Frequencies

GnomAD3 genomes AF: 0.000197 AC: 30 AN: 152160 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000228 AC: 57 AN: 250172 AF XY: 0.000192

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.000452

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000346 AC: 505 AN: 1461530 Hom.: 0 Cov.: 33 AF XY: 0.000338 AC XY: 246 AN XY: 727094

African (AFR) AF: 0.0000896 AC: 3 AN: 33470

American (AMR) AF: 0.0000672 AC: 3 AN: 44638

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86216

European-Finnish (FIN) AF: 0.0000749 AC: 4 AN: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000420 AC: 467 AN: 1111834

Other (OTH) AF: 0.000464 AC: 28 AN: 60394

GnomAD4 genome AF: 0.000197 AC: 30 AN: 152160 Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13 AN XY: 74326

African (AFR) AF: 0.0000724 AC: 3 AN: 41428

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000353 AC: 24 AN: 68024

Other (OTH) AF: 0.000478 AC: 1 AN: 2094

Alfa AF: 0.000356 Hom.: 0

Bravo AF: 0.000246

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000231 AC: 28

EpiCase AF: 0.000600

EpiControl AF: 0.000356

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

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	0.12
BayesDel_addAF	Uncertain	0.012	T
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	T
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	0.81	L
PhyloP100		4.9
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.20
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.046	D
Polyphen		1.0	D
Vest4		0.68
MVP		0.75
MPC		0.77
ClinPred		0.17	T
GERP RS		5.8
PromoterAI		-0.0031	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.48
gMVP		0.37
Mutation Taster		=42/58	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.23		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.23		Position offset: -9

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs139117230; hg19: chr11-64535270;