rs690016543

Positions:

• chr22-50465006-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_002972.4(SBF1):​c.1327G>A​(p.Asp443Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,712 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SBF1 NM_002972.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity no assertion criteria provided P:2 U:1
• Conservation: PhyloP100: 6.12

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.887

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SBF1	NM_002972.4	c.1327G>A	p.Asp443Asn	missense_variant	12/41	ENST00000380817.8	NP_002963.2
SBF1	NM_001410794.1	c.1330G>A	p.Asp444Asn	missense_variant	12/41		NP_001397723.1
SBF1	NM_001365819.1	c.1330G>A	p.Asp444Asn	missense_variant	12/40		NP_001352748.1
SBF1	NM_001410795.1	c.1327G>A	p.Asp443Asn	missense_variant	12/40		NP_001397724.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SBF1	ENST00000380817.8	c.1327G>A	p.Asp443Asn	missense_variant	12/41	1	NM_002972.4	ENSP00000370196	P3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461712 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 727162

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Charcot-Marie-Tooth disease Pathogenic:1 Uncertain:1

Uncertain significance, no assertion criteria provided	literature only	Inherited Neuropathy Consortium	-	- -
Likely pathogenic, no assertion criteria provided	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Dec 01, 2014	- -

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

Pathogenic, no assertion criteria provided

literature only

OMIM

May 06, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Uncertain	0.055	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	26
DANN	Uncertain	1.0
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.89	D;D
MetaSVM	Uncertain	0.79	D
MutationAssessor	Uncertain	2.7	M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-4.2	D;D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0040	D;D
Vest4		0.88
MutPred		0.36		.;Loss of helix (P = 0.1706);
MVP		0.97
ClinPred		0.99	D
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.58
gMVP		0.88

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: rs690016543; hg19: chr22-50903435;