1-149926400-A-G

Position:

• chr1-149926400-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_005850.5(SF3B4):​c.682T>C​(p.Leu228=) 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

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]

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 2480 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SF3B4	NM_005850.5	c.682T>C	p.Leu228=	synonymous_variant	3/6	ENST00000271628.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SF3B4	ENST00000271628.9	c.682T>C	p.Leu228=	synonymous_variant	3/6	1	NM_005850.5	P1
SF3B4	ENST00000457312.1	c.553T>C	p.Leu185=	synonymous_variant	3/3	5

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

GnomAD3 exomes AF: 0.0176 AC: 4398 AN: 250452 Hom.: 45 AF XY: 0.0180 AC XY: 2436 AN XY: 135312

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 SAS exome AF: 0.0128

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

Gnomad4 AFR exome AF: 0.00389

Gnomad4 AMR exome AF: 0.00952

Gnomad4 ASJ exome AF: 0.00376

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0130

Gnomad4 FIN exome AF: 0.0145

Gnomad4 NFE exome AF: 0.0278

Gnomad4 OTH exome AF: 0.0194

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

Gnomad4 AFR AF: 0.00450

Gnomad4 AMR AF: 0.0131

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0106

Gnomad4 FIN AF: 0.0139

Gnomad4 NFE AF: 0.0269

Gnomad4 OTH AF: 0.0204

Alfa AF: 0.0210 Hom.: 8

Bravo AF: 0.0155

Asia WGS AF: 0.00722 AC: 25 AN: 3478

EpiCase AF: 0.0287

EpiControl AF: 0.0266

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 22, 2021	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 02, 2024	- -

not specified Benign:2

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.24
DANN	Benign	0.52

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: rs115070660; hg19: chr1-149898292;