rs77518617

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_015559.3(SETBP1):c.4129G>C(p.Val1377Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0128 in 1,614,182 control chromosomes in the GnomAD database, including 162 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1377G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0090 ( 13 hom., cov: 32)

Exomes 𝑓: 0.013 ( 149 hom. )

Consequence

SETBP1
NM_015559.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 3.27

Publications

15 publications found

Variant links:

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]

SETBP1 Gene-Disease associations (from GenCC):

complex neurodevelopmental disorder
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
intellectual disability, autosomal dominant 29
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
Schinzel-Giedion syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Laboratory for Molecular Medicine, G2P, Labcorp Genetics (formerly Invitae), Orphanet
intellectual disability-expressive aphasia-facial dysmorphism syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

SETBP1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006798923).

BP6

Variant 18-45038613-G-C is Benign according to our data. Variant chr18-45038613-G-C is described in ClinVar as Benign. ClinVar VariationId is 159878.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00895 (1364/152336) while in subpopulation NFE AF = 0.0144 (979/68038). AF 95% confidence interval is 0.0136. There are 13 homozygotes in GnomAd4. There are 605 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 1364 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SETBP1	NM_015559.3 link	c.4129G>C	p.Val1377Leu	missense_variant	Exon 5 of 6	ENST00000649279.2	NP_056374.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SETBP1	ENST00000649279.2 link	c.4129G>C	p.Val1377Leu	missense_variant	Exon 5 of 6		NM_015559.3	ENSP00000497406.1

Frequencies

GnomAD3 genomes

AF:

0.00897

AC:

1365

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00309

Gnomad AMI

AF:

0.0482

Gnomad AMR

AF:

0.00753

Gnomad ASJ

AF:

0.0141

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00207

Gnomad FIN

AF:

0.00122

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0144

Gnomad OTH

AF:

0.0119

GnomAD2 exomes

AF:

0.00812

AC:

2041

AN:

251392

AF XY:

0.00837

show subpopulations

Gnomad AFR exome

AF:

0.00308

Gnomad AMR exome

AF:

0.00602

Gnomad ASJ exome

AF:

0.0130

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00226

Gnomad NFE exome

AF:

0.0130

Gnomad OTH exome

AF:

0.00863

GnomAD4 exome

AF:

0.0132

AC:

19329

AN:

1461846

Hom.:

149

Cov.:

AF XY:

0.0131

AC XY:

9513

AN XY:

727230

show subpopulations

African (AFR)

AF:

0.00320

AC:

107

AN:

33476

American (AMR)

AF:

0.00651

AC:

291

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.0118

AC:

309

AN:

26134

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39698

South Asian (SAS)

AF:

0.00320

AC:

276

AN:

86258

European-Finnish (FIN)

AF:

0.00236

AC:

126

AN:

53416

Middle Eastern (MID)

AF:

0.00399

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0157

AC:

17453

AN:

1111988

Other (OTH)

AF:

0.0123

AC:

742

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

1058

2115

3173

4230

5288

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

700

1400

2100

2800

3500

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00895

AC:

1364

AN:

152336

Hom.:

Cov.:

AF XY:

0.00812

AC XY:

605

AN XY:

74492

show subpopulations

African (AFR)

AF:

0.00308

AC:

128

AN:

41576

American (AMR)

AF:

0.00752

AC:

115

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0141

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00207

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00122

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0144

AC:

979

AN:

68038

Other (OTH)

AF:

0.0118

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

136

204

272

340

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0130

Hom.:

Bravo

AF:

0.00885

TwinsUK

AF:

0.0154

AC:

ALSPAC

AF:

0.0179

AC:

ESP6500AA

AF:

0.00522

AC:

ESP6500EA

AF:

0.0156

AC:

134

ExAC

AF:

0.00746

AC:

906

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.0129

EpiControl

AF:

0.0137

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

The SETBP1 p.Val1377Leu variant was not identified in the literature but was identified in dbSNP (ID: rs77518617), ClinVar (classified as benign by Genetic Services Laboratory, University of Chicago and likely benign by Illumina) and LOVD 3.0 (classified as likely benign and benign). The variant was identified in control databases in 2336 of 282752 chromosomes (16 homozygous) at a frequency of 0.008262 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 1719 of 129086 chromosomes (freq: 0.01332), Ashkenazi Jewish in 137 of 10366 chromosomes (freq: 0.01322), Other in 63 of 7228 chromosomes (freq: 0.008716), Latino in 213 of 35422 chromosomes (freq: 0.006013), African in 73 of 24968 chromosomes (freq: 0.002924), South Asian in 72 of 30614 chromosomes (freq: 0.002352) and European (Finnish) in 59 of 25116 chromosomes (freq: 0.002349), but was not observed in the East Asian population. The p.Val1377 residue is conserved across mammals and other organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Jul 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

SETBP1: BP4, BS1, BS2 -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 31681433) -

not specified

Benign:2

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 2024

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Schinzel-Giedion syndrome

Benign:1

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

SETBP1-related disorder

Benign:1

Dec 07, 2020

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.27

T;T

Eigen

Benign

-0.50

Eigen_PC

Benign

-0.37

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.76

.;T

MetaRNN

Benign

0.0068

T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

0.90

L;L

PhyloP100

3.3

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-0.58

.;N

REVEL

Benign

0.083

Sift

Benign

0.068

.;T

Sift4G

Benign

0.10

.;T

Polyphen

0.0030

B;B

Vest4

0.42

MutPred

0.21

Gain of glycosylation at P1376 (P = 0.0865);Gain of glycosylation at P1376 (P = 0.0865);

MVP

0.24

MPC

0.33

ClinPred

0.0027

GERP RS

4.1

Varity_R

0.050

gMVP

0.36

Mutation Taster

=99/1

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over