chr3-47121171-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_014159.7(SETD2):c.3465T>C(p.Asn1155Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.613 in 1,613,356 control chromosomes in the GnomAD database, including 305,165 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.65 ( 32842 hom., cov: 32)

Exomes 𝑓: 0.61 ( 272323 hom. )

Consequence

SETD2
NM_014159.7 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.0840

Publications

37 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BP6

Variant 3-47121171-A-G is Benign according to our data. Variant chr3-47121171-A-G is described in ClinVar as [Benign]. Clinvar id is 586533.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.084 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.75 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SETD2	NM_014159.7 link	c.3465T>C	p.Asn1155Asn	synonymous_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.3465T>C	p.Asn1155Asn	synonymous_variant	Exon 3 of 21	5	NM_014159.7	ENSP00000386759.3		Q9BYW2-1

Frequencies

GnomAD3 genomes

AF:

0.653

AC:

99148

AN:

151886

Hom.:

32781

Cov.:

show subpopulations

Gnomad AFR

AF:

0.757

Gnomad AMI

AF:

0.421

Gnomad AMR

AF:

0.665

Gnomad ASJ

AF:

0.593

Gnomad EAS

AF:

0.684

Gnomad SAS

AF:

0.604

Gnomad FIN

AF:

0.630

Gnomad MID

AF:

0.529

Gnomad NFE

AF:

0.599

Gnomad OTH

AF:

0.628

GnomAD2 exomes

AF:

0.638

AC:

159998

AN:

250966

AF XY:

0.626

show subpopulations

Gnomad AFR exome

AF:

0.766

Gnomad AMR exome

AF:

0.755

Gnomad ASJ exome

AF:

0.594

Gnomad EAS exome

AF:

0.679

Gnomad FIN exome

AF:

0.633

Gnomad NFE exome

AF:

0.594

Gnomad OTH exome

AF:

0.622

GnomAD4 exome

AF:

0.608

AC:

888970

AN:

1461350

Hom.:

272323

Cov.:

AF XY:

0.606

AC XY:

440308

AN XY:

726996

show subpopulations

African (AFR)

AF:

0.759

AC:

25407

AN:

33464

American (AMR)

AF:

0.742

AC:

33156

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.590

AC:

15413

AN:

26128

East Asian (EAS)

AF:

0.706

AC:

28044

AN:

39696

South Asian (SAS)

AF:

0.595

AC:

51357

AN:

86246

European-Finnish (FIN)

AF:

0.625

AC:

33403

AN:

53412

Middle Eastern (MID)

AF:

0.531

AC:

3064

AN:

5768

European-Non Finnish (NFE)

AF:

0.596

AC:

662280

AN:

1111542

Other (OTH)

AF:

0.610

AC:

36846

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

19625

39250

58874

78499

98124

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18170

36340

54510

72680

90850

<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:

0.653

AC:

99271

AN:

152006

Hom.:

32842

Cov.:

AF XY:

0.651

AC XY:

48363

AN XY:

74308

show subpopulations

African (AFR)

AF:

0.757

AC:

31392

AN:

41448

American (AMR)

AF:

0.665

AC:

10161

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.593

AC:

2055

AN:

3466

East Asian (EAS)

AF:

0.685

AC:

3548

AN:

5178

South Asian (SAS)

AF:

0.604

AC:

2909

AN:

4816

European-Finnish (FIN)

AF:

0.630

AC:

6650

AN:

10560

Middle Eastern (MID)

AF:

0.521

AC:

152

AN:

292

European-Non Finnish (NFE)

AF:

0.599

AC:

40692

AN:

67950

Other (OTH)

AF:

0.629

AC:

1330

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1734

3467

5201

6934

8668

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

778

1556

2334

3112

3890

<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:

0.617

Hom.:

97740

Bravo

AF:

0.663

Asia WGS

AF:

0.686

AC:

2385

AN:

3478

EpiCase

AF:

0.578

EpiControl

AF:

0.581

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Jul 05, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 20, 2017

Athena Diagnostics

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

- -

Luscan-Lumish syndrome

Benign:2

Jul 15, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

3.3

(source)

DANN

Benign

0.56

PhyloP100

0.084

PromoterAI

-0.031

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

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