22-50465004-ATC-GTT

Variant names:

• chr22-50465004-ATC-GTT
• NM_002972.4:c.1327_1329delGATinsAAC
• SBF1 p.Asp443Asn

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PS1_Moderate

The NM_002972.4(SBF1):​c.1327_1329delGATinsAAC​(p.Asp443Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Synonymous variant affecting the same amino acid position (i.e. D443D) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SBF1 NM_002972.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.12
• Publications: 0 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PS1: Transcript NM_002972.4 (SBF1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002972.4. 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
	SBF1	NM_002972.4	MANE Select	c.1327_1329delGATinsAAC	p.Asp443Asn	missense	N/A	NP_002963.2	O95248-5
	SBF1	NM_001410794.1		c.1330_1332delGATinsAAC	p.Asp444Asn	missense	N/A	NP_001397723.1	O95248-4
	SBF1	NM_001365819.1		c.1330_1332delGATinsAAC	p.Asp444Asn	missense	N/A	NP_001352748.1	O95248-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SBF1	ENST00000380817.8	TSL:1 MANE Select	c.1327_1329delGATinsAAC	p.Asp443Asn	missense	N/A	ENSP00000370196.2	O95248-5
	SBF1	ENST00000931646.1		c.1327_1329delGATinsAAC	p.Asp443Asn	missense	N/A	ENSP00000601705.1
	SBF1	ENST00000967446.1		c.1330_1332delGATinsAAC	p.Asp444Asn	missense	N/A	ENSP00000637505.1

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.1

Splicing

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

hg19: chr22-50903433;