chr11-9790651-C-T

Variant names:

• chr11-9790651-C-T
• rs546392558
• NM_030962.4:c.4603G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_030962.4(SBF2):​c.4603G>A​(p.Ala1535Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000699 in 1,431,372 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: SBF2 NM_030962.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.36
• 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-AS1 (HGNC:27438): (SBF2 antisense RNA 1)

LOC105369149 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11832735).

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.4603G>A	p.Ala1535Thr	missense	Exon 34 of 40	NP_112224.1	Q86WG5-1
	SBF2	NM_001386339.1		c.4699G>A	p.Ala1567Thr	missense	Exon 35 of 41	NP_001373268.1	A0A8I5KQ02
	SBF2	NM_001424318.1		c.4639G>A	p.Ala1547Thr	missense	Exon 35 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.4603G>A	p.Ala1535Thr	missense	Exon 34 of 40	ENSP00000256190.8	Q86WG5-1
	SBF2	ENST00000689128.1		c.4699G>A	p.Ala1567Thr	missense	Exon 35 of 41	ENSP00000509587.1	A0A8I5KQ02
	SBF2	ENST00000675281.2		c.4678G>A	p.Ala1560Thr	missense	Exon 35 of 41	ENSP00000502491.1	A0A6Q8PH13

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.99e-7 AC: 1 AN: 1431372 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 713144

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32766

American (AMR) AF: 0.00 AC: 0 AN: 44398

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25910

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39480

South Asian (SAS) AF: 0.00 AC: 0 AN: 84564

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53250

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5712

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1085852

Other (OTH) AF: 0.00 AC: 0 AN: 59440

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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	0.071
BayesDel_addAF	Benign	-0.038	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	22
DANN	Benign	0.93
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.21
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.061	D
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.52	T
MutationAssessor	Benign	0.13	N
PhyloP100		2.4
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.96	N
REVEL	Benign	0.22
Sift	Benign	0.34	T
Sift4G	Benign	0.32	T
Polyphen		0.015	B
Vest4		0.19
MutPred		0.32		Gain of phosphorylation at A1535 (P = 0.0292)
MVP		0.79
MPC		0.17
ClinPred		0.16	T
GERP RS		5.3
Varity_R		0.051
gMVP		0.30
Mutation Taster		=84/16	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs546392558; hg19: chr11-9812198;