rs115070660

Variant names:

• chr1-149926400-A-G
• rs115070660
• NM_005850.5:c.682T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_005850.5(SF3B4):​c.682T>C​(p.Leu228Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0231 in 1,611,792 control chromosomes in the GnomAD database, including 536 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (30 hom., cov: 32)
  • Exomes 𝑓: 0.024 (506 hom.)
• Consequence: SF3B4 NM_005850.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.08
• Publications: 6 publications found

Genes affected

SF3B4 (HGNC:10771): (splicing factor 3b subunit 4) This gene encodes one of four subunits of the splicing factor 3B. The protein encoded by this gene cross-links to a region in the pre-mRNA immediately upstream of the branchpoint sequence in pre-mRNA in the prespliceosomal complex A. It also may be involved in the assembly of the B, C and E spliceosomal complexes. In addition to RNA-binding activity, this protein interacts directly and highly specifically with subunit 2 of the splicing factor 3B. This protein contains two N-terminal RNA-recognition motifs (RRMs), consistent with the observation that it binds directly to pre-mRNA. [provided by RefSeq, Jul 2008]

SF3B4 Gene-Disease associations (from GenCC):

• Nager acrofacial dysostosis

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• SF3B4-related acrofacial dysostosis

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• acrofacial dysostosis Rodriguez type

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 1-149926400-A-G is Benign according to our data. Variant chr1-149926400-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 130291.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.08 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0163 (2480/152230) while in subpopulation NFE AF = 0.0269 (1828/67998). AF 95% confidence interval is 0.0259. There are 30 homozygotes in GnomAd4. There are 1188 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2480 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005850.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SF3B4	NM_005850.5	MANE Select	c.682T>C	p.Leu228Leu	synonymous	Exon 3 of 6	NP_005841.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SF3B4	ENST00000271628.9	TSL:1 MANE Select	c.682T>C	p.Leu228Leu	synonymous	Exon 3 of 6	ENSP00000271628.8
	SF3B4	ENST00000457312.1	TSL:5	c.553T>C	p.Leu185Leu	synonymous	Exon 3 of 3	ENSP00000391114.1

Frequencies

GnomAD3 genomes AF: 0.0163 AC: 2481 AN: 152112 Hom.: 30 Cov.: 32

Gnomad AFR AF: 0.00451

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.0131

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0108

Gnomad FIN AF: 0.0139

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0269

Gnomad OTH AF: 0.0206

GnomAD2 exomes AF: 0.0176 AC: 4398 AN: 250452 AF XY: 0.0180

Gnomad AFR exome AF: 0.00419

Gnomad AMR exome AF: 0.00988

Gnomad ASJ exome AF: 0.00420

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0151

Gnomad NFE exome AF: 0.0275

Gnomad OTH exome AF: 0.0188

GnomAD4 exome AF: 0.0238 AC: 34719 AN: 1459562 Hom.: 506 Cov.: 32 AF XY: 0.0234 AC XY: 16956 AN XY: 725610

African (AFR) AF: 0.00389 AC: 130 AN: 33440

American (AMR) AF: 0.00952 AC: 425 AN: 44632

Ashkenazi Jewish (ASJ) AF: 0.00376 AC: 98 AN: 26070

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39628

South Asian (SAS) AF: 0.0130 AC: 1124 AN: 86196

European-Finnish (FIN) AF: 0.0145 AC: 774 AN: 53400

Middle Eastern (MID) AF: 0.0163 AC: 94 AN: 5760

European-Non Finnish (NFE) AF: 0.0278 AC: 30899 AN: 1110142

Other (OTH) AF: 0.0194 AC: 1171 AN: 60294

GnomAD4 genome AF: 0.0163 AC: 2480 AN: 152230 Hom.: 30 Cov.: 32 AF XY: 0.0160 AC XY: 1188 AN XY: 74422

African (AFR) AF: 0.00450 AC: 187 AN: 41550

American (AMR) AF: 0.0131 AC: 200 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3466

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5180

South Asian (SAS) AF: 0.0106 AC: 51 AN: 4818

European-Finnish (FIN) AF: 0.0139 AC: 147 AN: 10608

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0269 AC: 1828 AN: 67998

Other (OTH) AF: 0.0204 AC: 43 AN: 2112

Alfa AF: 0.00799 Hom.: 8

Bravo AF: 0.0155

Asia WGS AF: 0.00722 AC: 25 AN: 3478

EpiCase AF: 0.0287

EpiControl AF: 0.0266

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.24
DANN	Benign	0.52
PhyloP100		-2.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs115070660; hg19: chr1-149898292;