rs1060499998

chr11-9832419-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_030962.4(SBF2):c.3457T>C(p.Tyr1153His) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SBF2 NM_030962.4 missense, splice_region
• Scores: Splicing: ADA: 0.9292
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.32

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SBF2	NM_030962.4	c.3457T>C	p.Tyr1153His	missense_variant, splice_region_variant	27/40	ENST00000256190.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SBF2	ENST00000256190.13	c.3457T>C	p.Tyr1153His	missense_variant, splice_region_variant	27/40	1	NM_030962.4	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Charcot-Marie-Tooth disease type 4 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 24, 2016

This variant has been observed on the opposite chromosome (in trans) from a pathogenic variant in an individual affected with hereditary motor and sensory neuropathy (Invitae database). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. In summary, this variant is a rare missense change with uncertain impact on protein function. While it is absent from the population and been observed in an affected individual, the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant is not present in population databases (ExAC no frequency). This sequence change replaces tyrosine with histidine at codon 1153 of the SBF2 protein (p.Tyr1153His). The tyrosine residue is highly conserved and there is a moderate physicochemical difference between tyrosine and histidine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.86	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.7	H
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.91
MutPred		0.88		Gain of disorder (P = 0.0617);
MVP		0.96
MPC		0.83
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.85
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.93
dbscSNV1_RF	Benign	0.46
SpliceAI score (max)		0.020		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: rs1060499998; hg19: chr11-9853966;