3-47101597-AGTGTGTGTGTGTGTGTGTGTGTGT-AGTGTGTGTGTGTGTGTGT

Position:

• chr3-47101597-AGTGTGTGTGTGTGTGTGTGTGTGT-AGTGTGTGTGTGTGTGTGT

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BS1 BS2

The NM_014159.7(SETD2):​c.4918-48_4918-43delACACAC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00731 in 732,570 control chromosomes in the GnomAD database, including 19 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.0085 (8 hom., cov: 0)
  • Exomes 𝑓: 0.0070 (11 hom.)
• Consequence: SETD2 NM_014159.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.06

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00848 (1201/141652) while in subpopulation AFR AF= 0.0178 (673/37872). AF 95% confidence interval is 0.0167. There are 8 homozygotes in gnomad4. There are 589 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1201 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SETD2	NM_014159.7	c.4918-48_4918-43delACACAC		intron_variant		ENST00000409792.4	NP_054878.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SETD2	ENST00000409792.4	c.4918-48_4918-43delACACAC		intron_variant		5	NM_014159.7	ENSP00000386759.3

Frequencies

GnomAD3 genomes AF: 0.00849 AC: 1202 AN: 141554 Hom.: 8 Cov.: 0

Gnomad AFR AF: 0.0178

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00995

Gnomad ASJ AF: 0.0467

Gnomad EAS AF: 0.00620

Gnomad SAS AF: 0.00780

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0197

Gnomad NFE AF: 0.00220

Gnomad OTH AF: 0.0109

GnomAD3 exomes AF: 0.0138 AC: 1682 AN: 122034 Hom.: 8 AF XY: 0.0125 AC XY: 828 AN XY: 66322

Gnomad AFR exome AF: 0.0203

Gnomad AMR exome AF: 0.0369

Gnomad ASJ exome AF: 0.0423

Gnomad EAS exome AF: 0.0265

Gnomad SAS exome AF: 0.0151

Gnomad FIN exome AF: 0.00224

Gnomad NFE exome AF: 0.00616

Gnomad OTH exome AF: 0.0127

GnomAD4 exome AF: 0.00702 AC: 4151 AN: 590918 Hom.: 11 AF XY: 0.00688 AC XY: 2167 AN XY: 314906

Gnomad4 AFR exome AF: 0.0154

Gnomad4 AMR exome AF: 0.0249

Gnomad4 ASJ exome AF: 0.0366

Gnomad4 EAS exome AF: 0.0173

Gnomad4 SAS exome AF: 0.00900

Gnomad4 FIN exome AF: 0.00222

Gnomad4 NFE exome AF: 0.00323

Gnomad4 OTH exome AF: 0.00882

GnomAD4 genome AF: 0.00848 AC: 1201 AN: 141652 Hom.: 8 Cov.: 0 AF XY: 0.00858 AC XY: 589 AN XY: 68662

Gnomad4 AFR AF: 0.0178

Gnomad4 AMR AF: 0.00993

Gnomad4 ASJ AF: 0.0467

Gnomad4 EAS AF: 0.00621

Gnomad4 SAS AF: 0.00735

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00220

Gnomad4 OTH AF: 0.0108

ClinVar

Not reported in ClinVar

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;