3-47101597-AGTGTGTGTGTGTGTGTGTGTGTGT-AGTGTGTGTGT

Position:

• chr3-47101597-AGTGTGTGTGTGTGTGTGTGTGTGT-AGTGTGTGTGT

Variant summary

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

The NM_014159.7(SETD2):​c.4918-56_4918-43del variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000184 in 734,096 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00012 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00020 (0 hom.)
• Consequence: SETD2 NM_014159.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.26

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 sas. gnomad4 allele frequency = 0.00012 (17/141670) while in subpopulation SAS AF= 0.000919 (4/4352). AF 95% confidence interval is 0.000314. There are 0 homozygotes in gnomad4. There are 9 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 17 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SETD2	NM_014159.7	c.4918-56_4918-43del		intron_variant		ENST00000409792.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SETD2	ENST00000409792.4	c.4918-56_4918-43del		intron_variant		5	NM_014159.7	P3

Frequencies

GnomAD3 genomes AF: 0.000120 AC: 17 AN: 141572 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000106

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000710

Gnomad ASJ AF: 0.000298

Gnomad EAS AF: 0.000207

Gnomad SAS AF: 0.000917

Gnomad FIN AF: 0.000109

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000770

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000199 AC: 118 AN: 592426 Hom.: 0 AF XY: 0.000266 AC XY: 84 AN XY: 315694

Gnomad4 AFR exome AF: 0.000137

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000626

Gnomad4 EAS exome AF: 0.0000952

Gnomad4 SAS exome AF: 0.00160

Gnomad4 FIN exome AF: 0.0000222

Gnomad4 NFE exome AF: 0.0000672

Gnomad4 OTH exome AF: 0.000136

GnomAD4 genome AF: 0.000120 AC: 17 AN: 141670 Hom.: 0 Cov.: 0 AF XY: 0.000131 AC XY: 9 AN XY: 68672

Gnomad4 AFR AF: 0.000106

Gnomad4 AMR AF: 0.0000709

Gnomad4 ASJ AF: 0.000298

Gnomad4 EAS AF: 0.000207

Gnomad4 SAS AF: 0.000919

Gnomad4 FIN AF: 0.000109

Gnomad4 NFE AF: 0.0000770

Gnomad4 OTH AF: 0.00

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;