3-47101597-AGTGTGTGTGTGTGTGTGTGTGTGT-AGTGTGTGTGTGTGTGTGTGTGTGTGTGTGT

Position:

• chr3-47101597-AGTGTGTGTGTGTGTGTGTGTGTGT-AGTGTGTGTGTGTGTGTGTGTGTGTGTGTGT

Variant summary

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

The NM_014159.7(SETD2):​c.4918-43_4918-42insACACAC variant causes a intron change involving the alteration of a non-conserved nucleotide. 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 0.0055 (3 hom., cov: 0)
  • Exomes 𝑓: 0.0022 (1 hom.)
• Consequence: SETD2 NM_014159.7 intron
• Clinical Significance: Not reported in ClinVar
• 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 -8 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00545 (772/141648) while in subpopulation AFR AF= 0.00792 (300/37866). AF 95% confidence interval is 0.00719. There are 3 homozygotes in gnomad4. There are 349 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 772 AD gene.

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.00544 AC: 770 AN: 141550 Hom.: 3 Cov.: 0

Gnomad AFR AF: 0.00789

Gnomad AMI AF: 0.00344

Gnomad AMR AF: 0.00476

Gnomad ASJ AF: 0.00298

Gnomad EAS AF: 0.00351

Gnomad SAS AF: 0.00550

Gnomad FIN AF: 0.000219

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00518

Gnomad OTH AF: 0.00673

GnomAD3 exomes AF: 0.00277 AC: 338 AN: 122034 Hom.: 4 AF XY: 0.00270 AC XY: 179 AN XY: 66322

Gnomad AFR exome AF: 0.00269

Gnomad AMR exome AF: 0.00299

Gnomad ASJ exome AF: 0.00155

Gnomad EAS exome AF: 0.00239

Gnomad SAS exome AF: 0.00275

Gnomad FIN exome AF: 0.000480

Gnomad NFE exome AF: 0.00335

Gnomad OTH exome AF: 0.00289

GnomAD4 exome AF: 0.00222 AC: 1317 AN: 592254 Hom.: 1 Cov.: 0 AF XY: 0.00231 AC XY: 730 AN XY: 315608

Gnomad4 AFR exome AF: 0.00185

Gnomad4 AMR exome AF: 0.00235

Gnomad4 ASJ exome AF: 0.00150

Gnomad4 EAS exome AF: 0.00203

Gnomad4 SAS exome AF: 0.00207

Gnomad4 FIN exome AF: 0.000777

Gnomad4 NFE exome AF: 0.00240

Gnomad4 OTH exome AF: 0.00316

GnomAD4 genome AF: 0.00545 AC: 772 AN: 141648 Hom.: 3 Cov.: 0 AF XY: 0.00508 AC XY: 349 AN XY: 68662

Gnomad4 AFR AF: 0.00792

Gnomad4 AMR AF: 0.00475

Gnomad4 ASJ AF: 0.00298

Gnomad4 EAS AF: 0.00352

Gnomad4 SAS AF: 0.00551

Gnomad4 FIN AF: 0.000219

Gnomad4 NFE AF: 0.00518

Gnomad4 OTH AF: 0.00666

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;