NM_030962.4:c.3001A>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_ModerateBS1_Supporting

The NM_030962.4(SBF2):​c.3001A>T​(p.Met1001Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000254 in 1,613,802 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M1001I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

SBF2
NM_030962.4 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 5.14

Publications

0 publications found
Variant links:
Genes affected
SBF2 (HGNC:2135): (SET binding factor 2) This gene encodes a pseudophosphatase and member of the myotubularin-related protein family. This gene maps within the CMT4B2 candidate region of chromosome 11p15 and mutations in this gene have been associated with Charcot-Marie-Tooth Disease, type 4B2. [provided by RefSeq, Jul 2008]
SBF2 Gene-Disease associations (from GenCC):
  • Charcot-Marie-Tooth disease type 4B2
    Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P, ClinGen, Ambry Genetics

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.17450267).
BS1
Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.0000267 (39/1461624) while in subpopulation SAS AF = 0.000441 (38/86250). AF 95% confidence interval is 0.00033. There are 0 homozygotes in GnomAdExome4. There are 28 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. 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
SBF2NM_030962.4 linkc.3001A>T p.Met1001Leu missense_variant Exon 24 of 40 ENST00000256190.13 NP_112224.1 Q86WG5-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SBF2ENST00000256190.13 linkc.3001A>T p.Met1001Leu missense_variant Exon 24 of 40 1 NM_030962.4 ENSP00000256190.8 Q86WG5-1

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152178
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000414
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000477
AC:
12
AN:
251326
AF XY:
0.0000810
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000267
AC:
39
AN:
1461624
Hom.:
0
Cov.:
31
AF XY:
0.0000385
AC XY:
28
AN XY:
727128
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33474
American (AMR)
AF:
0.00
AC:
0
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26126
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39686
South Asian (SAS)
AF:
0.000441
AC:
38
AN:
86250
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53418
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
8.99e-7
AC:
1
AN:
1111790
Other (OTH)
AF:
0.00
AC:
0
AN:
60388
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
3
6
8
11
14
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<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:
0.0000131
AC:
2
AN:
152178
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74356
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41440
American (AMR)
AF:
0.00
AC:
0
AN:
15274
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3468
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5200
South Asian (SAS)
AF:
0.000414
AC:
2
AN:
4828
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10626
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
68028
Other (OTH)
AF:
0.00
AC:
0
AN:
2086
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.550
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<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:
0.0000936
Hom.:
0
Bravo
AF:
0.0000151
ExAC
AF:
0.0000741
AC:
9

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Nov 25, 2020
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The p.M1001L variant (also known as c.3001A>T), located in coding exon 24 of the SBF2 gene, results from an A to T substitution at nucleotide position 3001. The methionine at codon 1001 is replaced by leucine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Charcot-Marie-Tooth disease type 4B2 Uncertain:1
Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Charcot-Marie-Tooth disease type 4 Uncertain:1
Sep 19, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces methionine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1001 of the SBF2 protein (p.Met1001Leu). This variant is present in population databases (rs781742897, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with SBF2-related conditions. ClinVar contains an entry for this variant (Variation ID: 306590). 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 SBF2 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.090
BayesDel_addAF
Benign
-0.15
T
BayesDel_noAF
Benign
-0.13
CADD
Benign
22
DANN
Benign
0.95
DEOGEN2
Benign
0.16
T
Eigen
Benign
-0.077
Eigen_PC
Benign
0.16
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Benign
0.70
T
M_CAP
Benign
0.019
T
MetaRNN
Benign
0.17
T
MetaSVM
Benign
-0.62
T
MutationAssessor
Benign
1.4
L
PhyloP100
5.1
PrimateAI
Uncertain
0.58
T
PROVEAN
Benign
-1.2
N
REVEL
Benign
0.28
Sift
Benign
0.18
T
Sift4G
Benign
0.090
T
Polyphen
0.057
B
Vest4
0.47
MutPred
0.43
Gain of methylation at K1002 (P = 0.0314);
MVP
0.72
MPC
0.17
ClinPred
0.076
T
GERP RS
6.0
Varity_R
0.14
gMVP
0.33
Mutation Taster
=90/10
polymorphism

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

Other links and lift over

dbSNP: rs781742897; hg19: chr11-9867221; API