22-50447346-A-G

Variant names:

• chr22-50447346-A-G
• rs1053744
• NM_002972.4:c.5559T>C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_002972.4(SBF1):​c.5559T>C​(p.Thr1853Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.528 in 1,613,434 control chromosomes in the GnomAD database, including 226,076 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.52 (20582 hom., cov: 33)
  • Exomes 𝑓: 0.53 (205494 hom.)
• Consequence: SBF1 NM_002972.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.0790
• Publications: 29 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.046).
• BP6: Variant 22-50447346-A-G is Benign according to our data. Variant chr22-50447346-A-G is described in ClinVar as Benign. ClinVar VariationId is 258881.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.079 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.538 is higher than 0.05.

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.5559T>C	p.Thr1853Thr	synonymous	Exon 40 of 41	NP_002963.2	O95248-5
	SBF1	NM_001410794.1		c.5562T>C	p.Thr1854Thr	synonymous	Exon 40 of 41	NP_001397723.1	O95248-4
	SBF1	NM_001365819.1		c.5484T>C	p.Thr1828Thr	synonymous	Exon 39 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.5559T>C	p.Thr1853Thr	synonymous	Exon 40 of 41	ENSP00000370196.2	O95248-5
	SBF1	ENST00000418590.4	TSL:1	c.1155T>C	p.Thr385Thr	synonymous	Exon 8 of 9	ENSP00000401538.2	H0Y5W8
	SBF1	ENST00000688381.1		c.680T>C	p.Leu227Pro	missense	Exon 5 of 6	ENSP00000508847.1	A0A8I5KUS0

Frequencies

GnomAD3 genomes AF: 0.520 AC: 78909 AN: 151888 Hom.: 20550 Cov.: 33

Gnomad AFR AF: 0.479

Gnomad AMI AF: 0.608

Gnomad AMR AF: 0.545

Gnomad ASJ AF: 0.580

Gnomad EAS AF: 0.462

Gnomad SAS AF: 0.456

Gnomad FIN AF: 0.512

Gnomad MID AF: 0.592

Gnomad NFE AF: 0.543

Gnomad OTH AF: 0.558

GnomAD2 exomes AF: 0.519 AC: 129468 AN: 249302 AF XY: 0.518

Gnomad AFR exome AF: 0.475

Gnomad AMR exome AF: 0.545

Gnomad ASJ exome AF: 0.582

Gnomad EAS exome AF: 0.450

Gnomad FIN exome AF: 0.514

Gnomad NFE exome AF: 0.540

Gnomad OTH exome AF: 0.533

GnomAD4 exome AF: 0.529 AC: 773485 AN: 1461428 Hom.: 205494 Cov.: 51 AF XY: 0.528 AC XY: 383667 AN XY: 727028

African (AFR) AF: 0.486 AC: 16282 AN: 33474

American (AMR) AF: 0.545 AC: 24375 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.574 AC: 15003 AN: 26128

East Asian (EAS) AF: 0.516 AC: 20472 AN: 39700

South Asian (SAS) AF: 0.459 AC: 39582 AN: 86254

European-Finnish (FIN) AF: 0.517 AC: 27550 AN: 53322

Middle Eastern (MID) AF: 0.536 AC: 3094 AN: 5768

European-Non Finnish (NFE) AF: 0.536 AC: 595823 AN: 1111684

Other (OTH) AF: 0.518 AC: 31304 AN: 60380

GnomAD4 genome AF: 0.520 AC: 78982 AN: 152006 Hom.: 20582 Cov.: 33 AF XY: 0.517 AC XY: 38443 AN XY: 74304

African (AFR) AF: 0.479 AC: 19884 AN: 41476

American (AMR) AF: 0.546 AC: 8347 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.580 AC: 2013 AN: 3468

East Asian (EAS) AF: 0.463 AC: 2378 AN: 5140

South Asian (SAS) AF: 0.456 AC: 2194 AN: 4814

European-Finnish (FIN) AF: 0.512 AC: 5420 AN: 10580

Middle Eastern (MID) AF: 0.588 AC: 173 AN: 294

European-Non Finnish (NFE) AF: 0.543 AC: 36854 AN: 67924

Other (OTH) AF: 0.553 AC: 1168 AN: 2112

Alfa AF: 0.538 Hom.: 37568

Bravo AF: 0.522

Asia WGS AF: 0.417 AC: 1454 AN: 3478

EpiCase AF: 0.547

EpiControl AF: 0.548

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Charcot-Marie-Tooth disease type 4B3 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	1.8
DANN	Benign	0.60
PhyloP100		0.079
Mutation Taster		=100/0	polymorphism (auto)

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: rs1053744; hg19: chr22-50885775; COSMIC: COSV53291520; COSMIC: COSV53291520;