rs151027707

chr22-50462555-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002972.4(SBF1):c.2127+4C>T variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00248 in 1,609,502 control chromosomes in the GnomAD database, including 59 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (29 hom., cov: 33)
  • Exomes 𝑓: 0.0017 (30 hom.)
• Consequence: SBF1 NM_002972.4 splice_donor_region, intron
• Scores: Splicing: ADA: 0.004438
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -3.07

Genes affected

SBF1 (HGNC:10542): (SET binding factor 1) This gene encodes a member of the protein-tyrosine phosphatase family. However, the encoded protein does not appear to be a catalytically active phosphatase because it lacks several amino acids in the catalytic pocket. This protein contains a Guanine nucleotide exchange factor (GEF) domain which is necessary for its role in growth and differentiation. Mutations in this gene have been associated with Charcot-Marie-Tooth disease 4B3. Pseudogenes of this gene have been defined on chromosomes 1 and 8. [provided by RefSeq, Dec 2014]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 22-50462555-G-A is Benign according to our data. Variant chr22-50462555-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 235427.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0101 (1538/152264) while in subpopulation AFR AF= 0.0326 (1356/41556). AF 95% confidence interval is 0.0312. There are 29 homozygotes in gnomad4. There are 734 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 29 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SBF1	NM_002972.4	c.2127+4C>T		splice_donor_region_variant, intron_variant		ENST00000380817.8
SBF1	NM_001365819.1	c.2130+4C>T		splice_donor_region_variant, intron_variant
SBF1	NM_001410794.1	c.2130+4C>T		splice_donor_region_variant, intron_variant
SBF1	NM_001410795.1	c.2127+4C>T		splice_donor_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SBF1	ENST00000380817.8	c.2127+4C>T		splice_donor_region_variant, intron_variant		1	NM_002972.4	P3

Frequencies

GnomAD3 genomes AF: 0.0101 AC: 1536 AN: 152148 Hom.: 29 Cov.: 33

Gnomad AFR AF: 0.0327

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00412

Gnomad ASJ AF: 0.0228

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000323

Gnomad OTH AF: 0.00718

GnomAD3 exomes AF: 0.00358 AC: 829 AN: 231880 Hom.: 10 AF XY: 0.00301 AC XY: 385 AN XY: 128038

Gnomad AFR exome AF: 0.0338

Gnomad AMR exome AF: 0.00182

Gnomad ASJ exome AF: 0.0255

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000100

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000539

Gnomad OTH exome AF: 0.00319

GnomAD4 exome AF: 0.00169 AC: 2459 AN: 1457238 Hom.: 30 Cov.: 34 AF XY: 0.00155 AC XY: 1121 AN XY: 724702

Gnomad4 AFR exome AF: 0.0346

Gnomad4 AMR exome AF: 0.00221

Gnomad4 ASJ exome AF: 0.0253

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.0000466

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000282

Gnomad4 OTH exome AF: 0.00351

GnomAD4 genome AF: 0.0101 AC: 1538 AN: 152264 Hom.: 29 Cov.: 33 AF XY: 0.00986 AC XY: 734 AN XY: 74450

Gnomad4 AFR AF: 0.0326

Gnomad4 AMR AF: 0.00412

Gnomad4 ASJ AF: 0.0228

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000324

Gnomad4 OTH AF: 0.00711

Alfa AF: 0.00726 Hom.: 8

Bravo AF: 0.0117

Asia WGS AF: 0.00346 AC: 12 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 05, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 14, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

Charcot-Marie-Tooth disease type 4B3 Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 07, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
Cadd	Benign	0.14
Dann	Benign	0.50

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0044
dbscSNV1_RF	Benign	0.32
SpliceAI score (max)		0.080		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: rs151027707; hg19: chr22-50900984;