chr22-50447066-A-G

Variant names:

• chr22-50447066-A-G
• rs1053764
• NM_002972.4:c.*76T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BS1 BS2

The NM_002972.4(SBF1):​c.*76T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0256 in 1,340,046 control chromosomes in the GnomAD database, including 609 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.017 (39 hom., cov: 33)
  • Exomes 𝑓: 0.027 (570 hom.)
• Consequence: SBF1 NM_002972.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.570
• Publications: 3 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: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, PanelApp Australia, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP6: Variant 22-50447066-A-G is Benign according to our data. Variant chr22-50447066-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 1219790.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0166 (2524/152170) while in subpopulation NFE AF = 0.0294 (1996/67962). AF 95% confidence interval is 0.0283. There are 39 homozygotes in GnomAd4. There are 1126 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 39 AR gene

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.*76T>C		3_prime_UTR	Exon 41 of 41	NP_002963.2	O95248-5
	SBF1	NM_001410794.1		c.*76T>C		3_prime_UTR	Exon 41 of 41	NP_001397723.1	O95248-4
	SBF1	NM_001365819.1		c.*76T>C		3_prime_UTR	Exon 40 of 40	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.*76T>C		3_prime_UTR	Exon 41 of 41	ENSP00000370196.2	O95248-5
	SBF1	ENST00000418590.4	TSL:1	c.*76T>C		3_prime_UTR	Exon 9 of 9	ENSP00000401538.2	H0Y5W8
	SBF1	ENST00000931646.1		c.*76T>C		3_prime_UTR	Exon 41 of 41	ENSP00000601705.1

Frequencies

GnomAD3 genomes AF: 0.0166 AC: 2525 AN: 152052 Hom.: 39 Cov.: 33

Gnomad AFR AF: 0.00486

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.00543

Gnomad ASJ AF: 0.00981

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.0162

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0294

Gnomad OTH AF: 0.0110

GnomAD4 exome AF: 0.0268 AC: 31830 AN: 1187876 Hom.: 570 Cov.: 16 AF XY: 0.0261 AC XY: 15475 AN XY: 592544

African (AFR) AF: 0.00478 AC: 132 AN: 27624

American (AMR) AF: 0.00462 AC: 161 AN: 34814

Ashkenazi Jewish (ASJ) AF: 0.0106 AC: 235 AN: 22234

East Asian (EAS) AF: 0.00 AC: 0 AN: 35284

South Asian (SAS) AF: 0.00262 AC: 192 AN: 73232

European-Finnish (FIN) AF: 0.0177 AC: 842 AN: 47490

Middle Eastern (MID) AF: 0.00419 AC: 15 AN: 3580

European-Non Finnish (NFE) AF: 0.0328 AC: 29249 AN: 892934

Other (OTH) AF: 0.0198 AC: 1004 AN: 50684

GnomAD4 genome AF: 0.0166 AC: 2524 AN: 152170 Hom.: 39 Cov.: 33 AF XY: 0.0151 AC XY: 1126 AN XY: 74426

African (AFR) AF: 0.00484 AC: 201 AN: 41508

American (AMR) AF: 0.00542 AC: 83 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00981 AC: 34 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4828

European-Finnish (FIN) AF: 0.0162 AC: 172 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0294 AC: 1996 AN: 67962

Other (OTH) AF: 0.0109 AC: 23 AN: 2112

Alfa AF: 0.0208 Hom.: 6

Bravo AF: 0.0161

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Benign	16
DANN	Benign	0.90
PhyloP100		0.57
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs1053764; hg19: chr22-50885495;