3-47062371-GTTTT-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_ModerateBS1BS2

The NM_014159.7(SETD2):c.6110-26delA variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★). There are indicators that this mutation may affect the branch point..

Frequency

Genomes: 𝑓 0.0035 ( 1 hom., cov: 0)

Exomes 𝑓: 0.050 ( 5 hom. )

Consequence

SETD2
NM_014159.7 intron

Scores

Not classified

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.577

Publications

3 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, STRONG Submitted by: PanelApp Australia, ClinGen
Rabin-Pappas syndrome
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
SETD2-related microcephaly-severe intellectual disability-multiple congenital anomalies syndrome
Inheritance: AD Classification: STRONG Submitted by: ClinGen, PanelApp Australia
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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP6

Variant 3-47062368-TTTGT-TTTG is Benign according to our data. Variant chr3-47062371-GT-G is described in ClinVar as Benign. ClinVar VariationId is 1178301.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00352 (516/146672) while in subpopulation AFR AF = 0.00885 (356/40226). AF 95% confidence interval is 0.00809. There are 1 homozygotes in GnomAd4. There are 215 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High AC in GnomAd4 at 516 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014159.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
SETD2	NM_014159.7	MANE Select	c.6110-26delA	intron	N/A	NP_054878.5
SETD2	NM_001349370.3		c.5978-26delA	intron	N/A	NP_001336299.1	A0A1W2PPX9
SETD2	NR_146158.3		n.6467-26delA	intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
SETD2	ENST00000409792.4	TSL:5 MANE Select	c.6110-26delA	intron	N/A	ENSP00000386759.3	Q9BYW2-1
SETD2	ENST00000330022.11	TSL:1	n.*1833-26delA	intron	N/A	ENSP00000332415.7	H7BXT4
SETD2	ENST00000952253.1		c.6032-26delA	intron	N/A	ENSP00000622312.1

Frequencies

GnomAD3 genomes

AF:

0.00351

AC:

514

AN:

146620

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00884

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00181

Gnomad ASJ

AF:

0.000588

Gnomad EAS

AF:

0.00316

Gnomad SAS

AF:

0.00238

Gnomad FIN

AF:

0.00210

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00112

Gnomad OTH

AF:

0.00494

GnomAD2 exomes

AF:

0.0373

AC:

5517

AN:

147998

AF XY:

0.0387

show subpopulations

Gnomad AFR exome

AF:

0.0384

Gnomad AMR exome

AF:

0.0341

Gnomad ASJ exome

AF:

0.0565

Gnomad EAS exome

AF:

0.0359

Gnomad FIN exome

AF:

0.0242

Gnomad NFE exome

AF:

0.0347

Gnomad OTH exome

AF:

0.0486

GnomAD4 exome

AF:

0.0503

AC:

55293

AN:

1099224

Hom.:

Cov.:

AF XY:

0.0502

AC XY:

27349

AN XY:

544416

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0733

AC:

1614

AN:

22024

American (AMR)

AF:

0.0348

AC:

866

AN:

24902

Ashkenazi Jewish (ASJ)

AF:

0.0467

AC:

840

AN:

17972

East Asian (EAS)

AF:

0.0338

AC:

1049

AN:

31052

South Asian (SAS)

AF:

0.0570

AC:

3412

AN:

59844

European-Finnish (FIN)

AF:

0.0371

AC:

1486

AN:

40106

Middle Eastern (MID)

AF:

0.0272

AC:

122

AN:

4488

European-Non Finnish (NFE)

AF:

0.0511

AC:

43626

AN:

853754

Other (OTH)

AF:

0.0505

AC:

2278

AN:

45082

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.269

Heterozygous variant carriers

6210

12420

18629

24839

31049

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1736

3472

5208

6944

8680

<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:

0.00352

AC:

516

AN:

146672

Hom.:

Cov.:

AF XY:

0.00301

AC XY:

215

AN XY:

71316

show subpopulations

African (AFR)

AF:

0.00885

AC:

356

AN:

40226

American (AMR)

AF:

0.00181

AC:

AN:

14896

Ashkenazi Jewish (ASJ)

AF:

0.000588

AC:

AN:

3404

East Asian (EAS)

AF:

0.00317

AC:

AN:

5054

South Asian (SAS)

AF:

0.00239

AC:

AN:

4610

European-Finnish (FIN)

AF:

0.00210

AC:

AN:

9044

Middle Eastern (MID)

AF:

0.00

AC:

AN:

282

European-Non Finnish (NFE)

AF:

0.00112

AC:

AN:

66240

Other (OTH)

AF:

0.00539

AC:

AN:

2040

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

107

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.000647

Hom.:

890

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.58

BranchPoint Hunter

3.0

Mutation Taster

=100/0

polymorphism

(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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over