3-47101597-AGTGTGTGTGTGTGTGTGTGTGTGT-AGTGTGTGTGTGTGTGTGTGTGTGTGTGT

Position:

• chr3-47101597-AGTGTGTGTGTGTGTGTGTGTGTGT-AGTGTGTGTGTGTGTGTGTGTGTGTGTGT

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_014159.7(SETD2):​c.4918-43_4918-42insACAC 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 0.031 (61 hom., cov: 0)
  • Exomes 𝑓: 0.016 (15 hom.)
• Consequence: SETD2 NM_014159.7 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.533

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP6: Variant 3-47101597-A-AGTGT is Benign according to our data. Variant chr3-47101597-A-AGTGT is described in ClinVar as [Likely_benign]. Clinvar id is 1220335.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0621 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SETD2	NM_014159.7	c.4918-43_4918-42insACAC		intron_variant		ENST00000409792.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SETD2	ENST00000409792.4	c.4918-43_4918-42insACAC		intron_variant		5	NM_014159.7	P3

Frequencies

GnomAD3 genomes AF: 0.0306 AC: 4334 AN: 141520 Hom.: 61 Cov.: 0

Gnomad AFR AF: 0.0306

Gnomad AMI AF: 0.0103

Gnomad AMR AF: 0.0298

Gnomad ASJ AF: 0.0167

Gnomad EAS AF: 0.0682

Gnomad SAS AF: 0.0305

Gnomad FIN AF: 0.0435

Gnomad MID AF: 0.0461

Gnomad NFE AF: 0.0271

Gnomad OTH AF: 0.0311

GnomAD3 exomes AF: 0.0184 AC: 2248 AN: 122034 Hom.: 24 AF XY: 0.0180 AC XY: 1197 AN XY: 66322

Gnomad AFR exome AF: 0.0189

Gnomad AMR exome AF: 0.0114

Gnomad ASJ exome AF: 0.00826

Gnomad EAS exome AF: 0.0380

Gnomad SAS exome AF: 0.0139

Gnomad FIN exome AF: 0.0278

Gnomad NFE exome AF: 0.0165

Gnomad OTH exome AF: 0.0174

GnomAD4 exome AF: 0.0157 AC: 9280 AN: 591338 Hom.: 15 Cov.: 0 AF XY: 0.0157 AC XY: 4951 AN XY: 315120

Gnomad4 AFR exome AF: 0.0196

Gnomad4 AMR exome AF: 0.0105

Gnomad4 ASJ exome AF: 0.0108

Gnomad4 EAS exome AF: 0.0492

Gnomad4 SAS exome AF: 0.0108

Gnomad4 FIN exome AF: 0.0279

Gnomad4 NFE exome AF: 0.0126

Gnomad4 OTH exome AF: 0.0149

GnomAD4 genome AF: 0.0307 AC: 4342 AN: 141618 Hom.: 61 Cov.: 0 AF XY: 0.0317 AC XY: 2176 AN XY: 68644

Gnomad4 AFR AF: 0.0307

Gnomad4 AMR AF: 0.0298

Gnomad4 ASJ AF: 0.0167

Gnomad4 EAS AF: 0.0682

Gnomad4 SAS AF: 0.0308

Gnomad4 FIN AF: 0.0435

Gnomad4 NFE AF: 0.0271

Gnomad4 OTH AF: 0.0323

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 10, 2019

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BranchPoint Hunter		4.0

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs61571386; hg19: chr3-47143087;