NM_030962.4:c.3761T>A

Variant names:

• chr11-9829388-A-T
• rs762211340
• NM_030962.4:c.3761T>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_030962.4(SBF2):​c.3761T>A​(p.Leu1254His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. L1254P) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SBF2 NM_030962.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.02
• Publications: 0 publications found

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: Labcorp Genetics (formerly Invitae), ClinGen, PanelApp Australia, Ambry Genetics, G2P, Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.873

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_030962.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SBF2	NM_030962.4	MANE Select	c.3761T>A	p.Leu1254His	missense	Exon 28 of 40	NP_112224.1	Q86WG5-1
	SBF2	NM_001386339.1		c.3761T>A	p.Leu1254His	missense	Exon 28 of 41	NP_001373268.1	A0A8I5KQ02
	SBF2	NM_001424318.1		c.3797T>A	p.Leu1266His	missense	Exon 29 of 41	NP_001411247.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SBF2	ENST00000256190.13	TSL:1 MANE Select	c.3761T>A	p.Leu1254His	missense	Exon 28 of 40	ENSP00000256190.8	Q86WG5-1
	SBF2	ENST00000689128.1		c.3761T>A	p.Leu1254His	missense	Exon 28 of 41	ENSP00000509587.1	A0A8I5KQ02
	SBF2	ENST00000675281.2		c.3761T>A	p.Leu1254His	missense	Exon 28 of 41	ENSP00000502491.1	A0A6Q8PH13

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Charcot-Marie-Tooth disease type 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
PhyloP100		5.0
Varity_R		0.34
gMVP		0.66
Mutation Taster		=79/21	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs762211340; hg19: chr11-9850935;