22-50456591-C-A

Variant names:

• chr22-50456591-C-A
• rs5771001
• NM_002972.4:c.3987G>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP7

The NM_002972.4(SBF1):​c.3987G>T​(p.Ala1329Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000144 in 1,391,858 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. A1329A) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SBF1 NM_002972.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.12
• Publications: 19 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: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31).
• BP7: Synonymous conserved (PhyloP=1.12 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SBF1	NM_002972.4	c.3987G>T	p.Ala1329Ala	synonymous_variant	Exon 30 of 41	ENST00000380817.8	NP_002963.2
SBF1	NM_001410794.1	c.3990G>T	p.Ala1330Ala	synonymous_variant	Exon 30 of 41		NP_001397723.1
SBF1	NM_001365819.1	c.3912G>T	p.Ala1304Ala	synonymous_variant	Exon 29 of 40		NP_001352748.1
SBF1	NM_001410795.1	c.3909G>T	p.Ala1303Ala	synonymous_variant	Exon 29 of 40		NP_001397724.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SBF1	ENST00000380817.8	c.3987G>T	p.Ala1329Ala	synonymous_variant	Exon 30 of 41	1	NM_002972.4	ENSP00000370196.2

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000144 AC: 2 AN: 1391858 Hom.: 0 Cov.: 40 AF XY: 0.00000146 AC XY: 1 AN XY: 686436

African (AFR) AF: 0.00 AC: 0 AN: 31588

American (AMR) AF: 0.00 AC: 0 AN: 35064

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22298

East Asian (EAS) AF: 0.00 AC: 0 AN: 37898

South Asian (SAS) AF: 0.0000133 AC: 1 AN: 74928

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48136

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5438

European-Non Finnish (NFE) AF: 9.27e-7 AC: 1 AN: 1079200

Other (OTH) AF: 0.00 AC: 0 AN: 57308

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
CADD	Benign	4.7
DANN	Benign	0.58
PhyloP100		1.1
PromoterAI		0.0060	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs5771001; hg19: chr22-50895020;