rs200488568

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBS1_Supporting

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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1590M) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00035 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00024 ( 1 hom. )

Consequence

SBF1
NM_002972.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:7

Conservation

PhyloP100: 1.20

Publications

10 publications found

Variant links:

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 Gene-Disease associations (from GenCC):

Charcot-Marie-Tooth disease type 4B3
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics

SBF1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.020742536).

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000355 (54/152200) while in subpopulation EAS AF = 0.00405 (21/5182). AF 95% confidence interval is 0.00271. There are 1 homozygotes in GnomAd4. There are 31 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SBF1	NM_002972.4 link	c.4768A>G	p.Thr1590Ala	missense_variant	Exon 35 of 41	ENST00000380817.8	NP_002963.2	O95248-5
SBF1	NM_001410794.1 link	c.4771A>G	p.Thr1591Ala	missense_variant	Exon 35 of 41		NP_001397723.1
SBF1	NM_001365819.1 link	c.4693A>G	p.Thr1565Ala	missense_variant	Exon 34 of 40		NP_001352748.1
SBF1	NM_001410795.1 link	c.4690A>G	p.Thr1564Ala	missense_variant	Exon 34 of 40		NP_001397724.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SBF1	ENST00000380817.8 link	c.4768A>G	p.Thr1590Ala	missense_variant	Exon 35 of 41	1	NM_002972.4	ENSP00000370196.2		O95248-5

Frequencies

GnomAD3 genomes

AF:

0.000342

AC:

AN:

152082

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.000333

AC:

AN:

249242

AF XY:

0.000310

show subpopulations

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 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.:

Cov.:

AF XY:

0.000254

AC XY:

185

AN XY:

727202

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33480

American (AMR)

AF:

0.000201

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00276

AC:

AN:

26134

East Asian (EAS)

AF:

0.00136

AC:

AN:

39700

South Asian (SAS)

AF:

0.000765

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53346

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000935

AC:

104

AN:

1111990

Other (OTH)

AF:

0.000613

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000355

AC:

AN:

152200

Hom.:

Cov.:

AF XY:

0.000417

AC XY:

AN XY:

74422

show subpopulations

African (AFR)

AF:

0.0000482

AC:

AN:

41528

American (AMR)

AF:

0.0000654

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00259

AC:

AN:

3472

East Asian (EAS)

AF:

0.00405

AC:

AN:

5182

South Asian (SAS)

AF:

0.000829

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000235

AC:

AN:

67972

Other (OTH)

AF:

0.000475

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.528

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000244

Hom.:

Bravo

AF:

0.000234

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000119

AC:

ExAC

AF:

0.000322

AC:

Asia WGS

AF:

0.00664

AC:

AN:

3478

EpiCase

AF:

0.000273

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:4

Mar 02, 2020

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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) -

Apr 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

SBF1: PP1:Strong -

May 14, 2020

AiLife Diagnostics, AiLife Diagnostics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 29, 2021

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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:1Uncertain:2

Jul 09, 2013

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Aug 18, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

Jan 09, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The SBF1 c.4768A>G; p.Thr1590Ala variant (rs200488568) is reported in the literature in three compound heterozygotes from a single family affected with Charcot-Marie-Tooth (CMT) type 4B3, and in a compound heterozygous individual without phenotype information (Nakhro 2013, Stranneheim 2021). This variant has also been found in a heterozygous individual with suspected CMT (Yalcintepe 2021). The p.Thr1590Ala variant is reported in ClinVar (Variation ID: 51006) and is found in the general population with an overall allele frequency of 0.03% (89/280,552 alleles) in the Genome Aggregation Database (v2.1.1). Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.274). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Nakhro K et al. SET binding factor 1 (SBF1) mutation causes Charcot-Marie-Tooth disease type 4B3. Neurology. 2013 Jul 9;81(2):165-73. PMID: 23749797. Stranneheim H et al. Integration of whole genome sequencing into a healthcare setting: high diagnostic rates across multiple clinical entities in 3219 rare disease patients. Genome Med. 2021 Mar 17;13(1):40. PMID: 33726816. Yalcintepe S et al. The Importance of Multiple Gene Analysis for Diagnosis and Differential Diagnosis in Charcot Marie Tooth Disease. Turk Neurosurg. 2021;31(6):888-895. PMID: 34169998. -

Tip-toe gait

Pathogenic:1

Jun 13, 2023

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

Significance:Likely pathogenic

Review Status:flagged submission

Collection Method:clinical testing

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

Aug 25, 2022

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

BayesDel_noAF

Benign

-0.26

CADD

Benign

(source)

DANN

Benign

0.96

Eigen

Benign

-0.54

Eigen_PC

Benign

-0.44

FATHMM_MKL

Benign

0.68

LIST_S2

Benign

0.70

T;T

M_CAP

Benign

0.075

MetaRNN

Benign

0.021

T;T

MetaSVM

Benign

-0.43

PhyloP100

1.2

PrimateAI

Uncertain

0.65

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

GERP RS

3.7

PromoterAI

0.0018

Neutral

(source)

Varity_R

0.095

gMVP

0.45

Mutation Taster

=4/96

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over