Genetic Variant SETD2:c.6110-26dupA (chr3-47062371-G-GT) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_ModerateBS1BS2

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

Frequency

Genomes: 𝑓 0.0013 ( 0 hom., cov: 0)

Exomes 𝑓: 0.033 ( 0 hom. )

Consequence

SETD2
NM_014159.7 intron

Scores

Not classified

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.577

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP6

Variant 3-47062371-G-GT is Benign according to our data. Variant chr3-47062371-G-GT is described in ClinVar as [Likely_benign]. Clinvar id is 1191604.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00131 (192/146764) while in subpopulation NFE AF= 0.00161 (107/66278). AF 95% confidence interval is 0.00137. There are 0 homozygotes in gnomad4. There are 88 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.

BS2

High AC in GnomAd4 at 192 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SETD2	NM_014159.7 link	c.6110-26dupA		intron_variant	Intron 13 of 20	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.6110-26_6110-25insA		intron_variant	Intron 13 of 20	5	NM_014159.7	ENSP00000386759.3		Q9BYW2-1

Frequencies

GnomAD3 genomes

AF:

0.00131

AC:

192

AN:

146712

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000971

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00107

Gnomad ASJ

AF:

0.000880

Gnomad EAS

AF:

0.000790

Gnomad SAS

AF:

0.000864

Gnomad FIN

AF:

0.00188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00161

Gnomad OTH

AF:

0.000987

GnomAD3 exomes

AF:

0.0156

AC:

2307

AN:

147998

Hom.:

AF XY:

0.0160

AC XY:

1286

AN XY:

80146

show subpopulations

Gnomad AFR exome

AF:

0.00616

Gnomad AMR exome

AF:

0.0112

Gnomad ASJ exome

AF:

0.0235

Gnomad EAS exome

AF:

0.0143

Gnomad SAS exome

AF:

0.0249

Gnomad FIN exome

AF:

0.0127

Gnomad NFE exome

AF:

0.0160

Gnomad OTH exome

AF:

0.0200

GnomAD4 exome

AF:

0.0326

AC:

38926

AN:

1194550

Hom.:

Cov.:

AF XY:

0.0325

AC XY:

19271

AN XY:

592128

show subpopulations

Gnomad4 AFR exome

AF:

0.0130

Gnomad4 AMR exome

AF:

0.0142

Gnomad4 ASJ exome

AF:

0.0332

Gnomad4 EAS exome

AF:

0.0161

Gnomad4 SAS exome

AF:

0.0347

Gnomad4 FIN exome

AF:

0.0217

Gnomad4 NFE exome

AF:

0.0347

Gnomad4 OTH exome

AF:

0.0320

GnomAD4 genome

AF:

0.00131

AC:

192

AN:

146764

Hom.:

Cov.:

AF XY:

0.00123

AC XY:

AN XY:

71386

show subpopulations

Gnomad4 AFR

AF:

0.000969

Gnomad4 AMR

AF:

0.00107

Gnomad4 ASJ

AF:

0.000880

Gnomad4 EAS

AF:

0.000792

Gnomad4 SAS

AF:

0.000868

Gnomad4 FIN

AF:

0.00188

Gnomad4 NFE

AF:

0.00161

Gnomad4 OTH

AF:

0.000979

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Sep 23, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BranchPoint Hunter

1.0

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

3-47062371-GTTTTTTT-GTTTTTTTT

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over