18-44876705-C-CTCTT

Variant names:

• chr18-44876705-C-CTCTT
• rs3085861
• ENST00000426838.8:c.681_682insTCTT

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 4P and 16B. PVS1_Strong BP6_Very_Strong BA1

The NM_001130110.2(SETBP1):​c.681_682insTCTT​(p.Thr228SerfsTer8) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.546 in 1,546,794 control chromosomes in the GnomAD database, including 232,434 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.54 (21965 hom., cov: 0)
  • Exomes 𝑓: 0.55 (210469 hom.)
• Consequence: SETBP1 NM_001130110.2 frameshift
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.28

Genes affected

SETBP1 (HGNC:15573): (SET binding protein 1) This gene encodes a protein which contains a several motifs including a ski homology region and a SET-binding region in addition to three nuclear localization signals. The encoded protein has been shown to bind the SET nuclear oncogene which is involved in DNA replication. Mutations in this gene are associated with Schinzel-Giedion midface retraction syndrome. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2011]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 4 pathogenic variants in the truncated region.
• BP6: Variant 18-44876705-C-CTCTT is Benign according to our data. Variant chr18-44876705-C-CTCTT is described in ClinVar as [Benign]. Clinvar id is 326725.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.548 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SETBP1	NM_015559.3	c.540+7422_540+7423insTCTT		intron_variant	Intron 3 of 5	ENST00000649279.2	NP_056374.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SETBP1	ENST00000649279.2	c.540+7422_540+7423insTCTT		intron_variant	Intron 3 of 5		NM_015559.3	ENSP00000497406.1

Frequencies

GnomAD3 genomes AF: 0.538 AC: 81389 AN: 151334 Hom.: 21949 Cov.: 0

Gnomad AFR AF: 0.532

Gnomad AMI AF: 0.652

Gnomad AMR AF: 0.498

Gnomad ASJ AF: 0.585

Gnomad EAS AF: 0.482

Gnomad SAS AF: 0.415

Gnomad FIN AF: 0.589

Gnomad MID AF: 0.541

Gnomad NFE AF: 0.552

Gnomad OTH AF: 0.514

GnomAD3 exomes AF: 0.522 AC: 80825 AN: 154924 Hom.: 21347 AF XY: 0.516 AC XY: 42338 AN XY: 82106

Gnomad AFR exome AF: 0.535

Gnomad AMR exome AF: 0.477

Gnomad ASJ exome AF: 0.590

Gnomad EAS exome AF: 0.500

Gnomad SAS exome AF: 0.423

Gnomad FIN exome AF: 0.595

Gnomad NFE exome AF: 0.550

Gnomad OTH exome AF: 0.514

GnomAD4 exome AF: 0.547 AC: 763310 AN: 1395344 Hom.: 210469 Cov.: 32 AF XY: 0.544 AC XY: 374055 AN XY: 688230

Gnomad4 AFR exome AF: 0.537

Gnomad4 AMR exome AF: 0.469

Gnomad4 ASJ exome AF: 0.591

Gnomad4 EAS exome AF: 0.480

Gnomad4 SAS exome AF: 0.428

Gnomad4 FIN exome AF: 0.590

Gnomad4 NFE exome AF: 0.559

Gnomad4 OTH exome AF: 0.537

GnomAD4 genome AF: 0.538 AC: 81458 AN: 151450 Hom.: 21965 Cov.: 0 AF XY: 0.536 AC XY: 39626 AN XY: 73974

Gnomad4 AFR AF: 0.531

Gnomad4 AMR AF: 0.499

Gnomad4 ASJ AF: 0.585

Gnomad4 EAS AF: 0.481

Gnomad4 SAS AF: 0.416

Gnomad4 FIN AF: 0.589

Gnomad4 NFE AF: 0.552

Gnomad4 OTH AF: 0.520

Alfa AF: 0.538 Hom.: 13187

Asia WGS AF: 0.490 AC: 1709 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency in ESP (all): 3542/6628=53.43% -

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 63% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 59. Only high quality variants are reported. -

Schinzel-Giedion syndrome Benign:2

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Nov 22, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 19, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs3085861; hg19: chr18-42456670; COSMIC: COSV56311994; COSMIC: COSV56311994;