22-50447194-G-A

Position:

• chr22-50447194-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_002972.4(SBF1):​c.5630C>T​(p.Pro1877Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00101 in 1,613,734 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00085 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0010 (6 hom.)
• Consequence: SBF1 NM_002972.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.0110

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]

SBF1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005461335).
• BP6: Variant 22-50447194-G-A is Benign according to our data. Variant chr22-50447194-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 707840.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SBF1	NM_002972.4	c.5630C>T	p.Pro1877Leu	missense_variant	41/41	ENST00000380817.8	NP_002963.2
SBF1	NM_001410794.1	c.5633C>T	p.Pro1878Leu	missense_variant	41/41		NP_001397723.1
SBF1	NM_001365819.1	c.5555C>T	p.Pro1852Leu	missense_variant	40/40		NP_001352748.1
SBF1	NM_001410795.1	c.5552C>T	p.Pro1851Leu	missense_variant	40/40		NP_001397724.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SBF1	ENST00000380817.8	c.5630C>T	p.Pro1877Leu	missense_variant	41/41	1	NM_002972.4	ENSP00000370196.2

Frequencies

GnomAD3 genomes AF: 0.000854 AC: 130 AN: 152238 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.0253

Gnomad AMR AF: 0.000654

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00101

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.000951 AC: 236 AN: 248086 Hom.: 1 AF XY: 0.00113 AC XY: 152 AN XY: 134998

Gnomad AFR exome AF: 0.000196

Gnomad AMR exome AF: 0.000696

Gnomad ASJ exome AF: 0.000601

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00219

Gnomad FIN exome AF: 0.0000468

Gnomad NFE exome AF: 0.00112

Gnomad OTH exome AF: 0.00150

GnomAD4 exome AF: 0.00102 AC: 1492 AN: 1461378 Hom.: 6 Cov.: 32 AF XY: 0.00109 AC XY: 789 AN XY: 727010

Gnomad4 AFR exome AF: 0.000329

Gnomad4 AMR exome AF: 0.000783

Gnomad4 ASJ exome AF: 0.000574

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00274

Gnomad4 FIN exome AF: 0.0000189

Gnomad4 NFE exome AF: 0.000978

Gnomad4 OTH exome AF: 0.00142

GnomAD4 genome AF: 0.000853 AC: 130 AN: 152356 Hom.: 1 Cov.: 33 AF XY: 0.000967 AC XY: 72 AN XY: 74492

Gnomad4 AFR AF: 0.000216

Gnomad4 AMR AF: 0.000653

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00101

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.000977 Hom.: 0

Bravo AF: 0.000963

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000837 AC: 7

ExAC AF: 0.000826 AC: 100

EpiCase AF: 0.00158

EpiControl AF: 0.00190

ClinVar

Significance: Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 16, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 27, 2024	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	SBF1: BS2 -

SBF1-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 26, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	17
DANN	Benign	0.94
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.072	N
LIST_S2	Uncertain	0.91	D;D
MetaRNN	Benign	0.0055	T;T
MetaSVM	Benign	-0.98	T
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-2.2	N;N
REVEL	Benign	0.10
Sift	Benign	0.36	T;T
Sift4G	Benign	0.31	T;T
Vest4		0.11
MVP		0.19
ClinPred		0.017	T
GERP RS		1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.049
gMVP		0.20

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: rs200103683; hg19: chr22-50885623;