rs76208147

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_014159.7(SETD2):c.3240G>A(p.Met1080Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0285 in 1,610,088 control chromosomes in the GnomAD database, including 2,182 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M1080T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.030 ( 232 hom., cov: 32)

Exomes 𝑓: 0.028 ( 1950 hom. )

Consequence

SETD2
NM_014159.7 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4O:1

Conservation

PhyloP100: 1.13

Publications

32 publications found

Variant links:

Genes affected

SETD2 (HGNC:18420): (SET domain containing 2, histone lysine methyltransferase) Huntington's disease (HD), a neurodegenerative disorder characterized by loss of striatal neurons, is caused by an expansion of a polyglutamine tract in the HD protein huntingtin. This gene encodes a protein belonging to a class of huntingtin interacting proteins characterized by WW motifs. This protein is a histone methyltransferase that is specific for lysine-36 of histone H3, and methylation of this residue is associated with active chromatin. This protein also contains a novel transcriptional activation domain and has been found associated with hyperphosphorylated RNA polymerase II. [provided by RefSeq, Aug 2008]

SETD2 Gene-Disease associations (from GenCC):

Luscan-Lumish syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
SETD2-related neurodevelopmental disorder without or with macrocephaly/overgrowth
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
Rabin-Pappas syndrome
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
SETD2-related microcephaly-severe intellectual disability-multiple congenital anomalies syndrome
Inheritance: AD Classification: STRONG Submitted by: ClinGen
Sotos syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
intellectual developmental disorder, autosomal dominant 70
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

SETD2 links:

ENSG00000296084 (HGNC:):

ENSG00000296084 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=0.0012949705).

BP6

Variant 3-47121396-C-T is Benign according to our data. Variant chr3-47121396-C-T is described in ClinVar as Benign. ClinVar VariationId is 135235.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.123 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SETD2	NM_014159.7 link	c.3240G>A	p.Met1080Ile	missense_variant	Exon 3 of 21	ENST00000409792.4	NP_054878.5	Q9BYW2-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SETD2	ENST00000409792.4 link	c.3240G>A	p.Met1080Ile	missense_variant	Exon 3 of 21	5	NM_014159.7	ENSP00000386759.3		Q9BYW2-1

Frequencies

GnomAD3 genomes

AF:

0.0304

AC:

4628

AN:

152080

Hom.:

230

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00780

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.117

Gnomad ASJ

AF:

0.0617

Gnomad EAS

AF:

0.131

Gnomad SAS

AF:

0.0495

Gnomad FIN

AF:

0.0144

Gnomad MID

AF:

0.0506

Gnomad NFE

AF:

0.0171

Gnomad OTH

AF:

0.0282

GnomAD2 exomes

AF:

0.0617

AC:

15294

AN:

248052

AF XY:

0.0543

show subpopulations

Gnomad AFR exome

AF:

0.00813

Gnomad AMR exome

AF:

0.229

Gnomad ASJ exome

AF:

0.0616

Gnomad EAS exome

AF:

0.136

Gnomad FIN exome

AF:

0.0180

Gnomad NFE exome

AF:

0.0192

Gnomad OTH exome

AF:

0.0456

GnomAD4 exome

AF:

0.0283

AC:

41320

AN:

1457890

Hom.:

1950

Cov.:

AF XY:

0.0280

AC XY:

20315

AN XY:

725434

show subpopulations

African (AFR)

AF:

0.00651

AC:

218

AN:

33480

American (AMR)

AF:

0.214

AC:

9567

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0618

AC:

1615

AN:

26132

East Asian (EAS)

AF:

0.144

AC:

5697

AN:

39690

South Asian (SAS)

AF:

0.0420

AC:

3627

AN:

86256

European-Finnish (FIN)

AF:

0.0185

AC:

914

AN:

49494

Middle Eastern (MID)

AF:

0.0414

AC:

239

AN:

5768

European-Non Finnish (NFE)

AF:

0.0159

AC:

17644

AN:

1111982

Other (OTH)

AF:

0.0298

AC:

1799

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

2417

4834

7252

9669

12086

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

878

1756

2634

3512

4390

<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:

0.0305

AC:

4642

AN:

152198

Hom.:

232

Cov.:

AF XY:

0.0332

AC XY:

2473

AN XY:

74396

show subpopulations

African (AFR)

AF:

0.00792

AC:

329

AN:

41528

American (AMR)

AF:

0.117

AC:

1789

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0617

AC:

214

AN:

3470

East Asian (EAS)

AF:

0.131

AC:

680

AN:

5178

South Asian (SAS)

AF:

0.0495

AC:

238

AN:

4808

European-Finnish (FIN)

AF:

0.0144

AC:

153

AN:

10604

Middle Eastern (MID)

AF:

0.0544

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0171

AC:

1161

AN:

68002

Other (OTH)

AF:

0.0284

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

204

408

611

815

1019

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

150

200

250

<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:

0.0265

Hom.:

440

Bravo

AF:

0.0398

TwinsUK

AF:

0.0151

AC:

ALSPAC

AF:

0.0158

AC:

ESP6500AA

AF:

0.00908

AC:

ESP6500EA

AF:

0.0195

AC:

168

ExAC

AF:

0.0539

AC:

6543

Asia WGS

AF:

0.0600

AC:

208

AN:

3478

EpiCase

AF:

0.0207

EpiControl

AF:

0.0191

ClinVar

Significance: Benign

Submissions summary: Benign:4Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Luscan-Lumish syndrome

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 15, 2022

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jul 21, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 28146470) -

not specified

Other:1

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.25

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.12

T;T

Eigen

Benign

-0.14

Eigen_PC

Benign

0.056

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.88

D;T

MetaRNN

Benign

0.0013

T;T

MetaSVM

Benign

-0.86

MutationAssessor

Benign

1.0

L;.

PhyloP100

1.1

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.96

N;N

REVEL

Benign

0.068

Sift

Uncertain

0.014

D;T

Sift4G

Benign

0.28

T;.

Polyphen

0.013

B;.

Vest4

0.10

MutPred

0.15

Gain of sheet (P = 0.0221);.;

MPC

0.28

ClinPred

0.013

GERP RS

5.2

PromoterAI

-0.013

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.36

gMVP

0.088

Mutation Taster

=93/7

polymorphism (auto)

(source)

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

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