rs200488568

Positions:

• chr22-50454858-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP5 BP4

The NM_002972.4(SBF1):​c.4768A>G​(p.Thr1590Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000247 in 1,613,988 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00035 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00024 (1 hom.)
• Consequence: SBF1 NM_002972.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:5
• Conservation: PhyloP100: 1.20

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 0 ACMG points.

• PP5: Variant 22-50454858-T-C is Pathogenic according to our data. Variant chr22-50454858-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 51006.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=5, Pathogenic=1}. Variant chr22-50454858-T-C is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.020742536). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SBF1	NM_002972.4	c.4768A>G	p.Thr1590Ala	missense_variant	35/41	ENST00000380817.8	NP_002963.2
SBF1	NM_001410794.1	c.4771A>G	p.Thr1591Ala	missense_variant	35/41		NP_001397723.1
SBF1	NM_001365819.1	c.4693A>G	p.Thr1565Ala	missense_variant	34/40		NP_001352748.1
SBF1	NM_001410795.1	c.4690A>G	p.Thr1564Ala	missense_variant	34/40		NP_001397724.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SBF1	ENST00000380817.8	c.4768A>G	p.Thr1590Ala	missense_variant	35/41	1	NM_002972.4	ENSP00000370196	P3

Frequencies

GnomAD3 genomes AF: 0.000342 AC: 52 AN: 152082 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00385

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.000480

GnomAD3 exomes AF: 0.000333 AC: 83 AN: 249242 Hom.: 0 AF XY: 0.000310 AC XY: 42 AN XY: 135272

Gnomad AFR exome AF: 0.0000647

Gnomad AMR exome AF: 0.000232

Gnomad ASJ exome AF: 0.00268

Gnomad EAS exome AF: 0.000501

Gnomad SAS exome AF: 0.000588

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000141

Gnomad OTH exome AF: 0.000660

GnomAD4 exome AF: 0.000235 AC: 344 AN: 1461788 Hom.: 1 Cov.: 33 AF XY: 0.000254 AC XY: 185 AN XY: 727202

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000201

Gnomad4 ASJ exome AF: 0.00276

Gnomad4 EAS exome AF: 0.00136

Gnomad4 SAS exome AF: 0.000765

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000935

Gnomad4 OTH exome AF: 0.000613

GnomAD4 genome AF: 0.000355 AC: 54 AN: 152200 Hom.: 1 Cov.: 33 AF XY: 0.000417 AC XY: 31 AN XY: 74422

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00259

Gnomad4 EAS AF: 0.00405

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.000475

Alfa AF: 0.000243 Hom.: 0

Bravo AF: 0.000234

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000119 AC: 1

ExAC AF: 0.000322 AC: 39

Asia WGS AF: 0.00664 AC: 23 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 02, 2020	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31070812, 30039846, 25496518, 23749797) -
Uncertain significance, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	May 14, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 29, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	SBF1: PP1:Strong -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2023	This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 1590 of the SBF1 protein (p.Thr1590Ala). This variant is present in population databases (rs200488568, gnomAD 0.3%). This missense change has been observed in individual(s) with Charcot-Marie-Tooth disease type 4B3 (PMID: 23749797). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 51006). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SBF1 protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -

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

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 09, 2013

- -

Tip-toe gait Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino

Jun 13, 2023

Hereditary motor sensory neuropathy (HMSN), also known as Charcot-Marie-Tooth Disease (CMT), is the most commonly inherited peripheral polyneuropathy. It constitutes a group of inherited, progressive, motor and sensory peripheral nerve disorders with properties of demyelination, axonal degeneration, or both. It is classified by clinical characteristics, modes of inheritance, electrophysiologic features, metabolic defects, and specific gene markers. Our patients all walk on tiptoe, so they show similar symptoms. When we genetically test them with our toe walking panel, we find that around 90 per cent of them have a genetic variant that explains their toe walking. These can be assigned, for example, to the area of myopathies (such as variants of the COL6A3 gene), the area of hereditary neuropathies (such as variants of the KMT2C gene) or the area of metabolic diseases (such as variants of the PYGM gene). In a smaller group of patients with almost identical symptoms, no abnormality is found in the genes of our panel, but spastic paraplegia can be detected. In another small group of our toe walkers, no abnormalities can be detected in the genes analysed in our toe walking panel, nor do they suffer from spastic paraplegia, as is also the case with healthy children. In contrast to these, however, they show a tiptoe gait. These patients suffer from infantile cerebral palsy, in which toe walking can also be observed. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 25, 2022

Variant summary: SBF1 c.4768A>G (p.Thr1590Ala) results in a non-conservative amino acid change located in the Myotubularin-like, phosphatase domain (IPR010569) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00033 in 249242 control chromosomes. This frequency does not allow conclusions about variant significance. c.4768A>G has been reported in the literature as a compound heterozygous genotype in at-least three individuals from a single family affected with autosomal recessive demyelinating Charcot-Marie- Tooth disease type 4B (CMT4B) and as a non-informative genotype (uncertainty regarding the second reported allele and no traceable clinical case evidence) in another study examining whole genome sequencing into a healthcare setting (example, Nakhro_2013, Stranneheim_2021). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (Likely pathogenic/Pathogenic, n=2; VUS, n=3). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	20
DANN	Benign	0.96
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.70	T;T
M_CAP	Benign	0.075	D
MetaRNN	Benign	0.021	T;T
MetaSVM	Benign	-0.43	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-1.7	N;N
REVEL	Benign	0.27
Sift	Benign	0.12	T;T
Sift4G	Benign	0.10	T;T
Vest4		0.45
MVP		0.48
ClinPred		0.0097	T
GERP RS		3.7
Varity_R		0.095
gMVP		0.45

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: rs200488568; hg19: chr22-50893287; COSMIC: COSV62365823; COSMIC: COSV62365823;