3-47101597-AGTGTGTGTGTGTGTGTGTGTGTGT-AGTGTGTGTGTGT

Position:

• chr3-47101597-AGTGTGTGTGTGTGTGTGTGTGTGT-AGTGTGTGTGTGT

Variant summary

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

The NM_014159.7(SETD2):​c.4918-54_4918-43del variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000509 in 734,100 control chromosomes in the GnomAD database, including 1 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 0.0015 (1 hom., cov: 0)
  • Exomes 𝑓: 0.00026 (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 afr. gnomad4 allele frequency = 0.00155 (219/141670) while in subpopulation AFR AF= 0.00473 (179/37878). AF 95% confidence interval is 0.00416. There are 1 homozygotes in gnomad4. There are 103 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 219 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SETD2	NM_014159.7	c.4918-54_4918-43del		intron_variant		ENST00000409792.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SETD2	ENST00000409792.4	c.4918-54_4918-43del		intron_variant		5	NM_014159.7	P3

Frequencies

GnomAD3 genomes AF: 0.00154 AC: 218 AN: 141572 Hom.: 1 Cov.: 0

Gnomad AFR AF: 0.00471

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00107

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00330

Gnomad SAS AF: 0.000917

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000616

Gnomad OTH AF: 0.000518

GnomAD4 exome AF: 0.000262 AC: 155 AN: 592430 Hom.: 0 AF XY: 0.000241 AC XY: 76 AN XY: 315696

Gnomad4 AFR exome AF: 0.00377

Gnomad4 AMR exome AF: 0.000403

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00171

Gnomad4 SAS exome AF: 0.000176

Gnomad4 FIN exome AF: 0.0000222

Gnomad4 NFE exome AF: 0.0000457

Gnomad4 OTH exome AF: 0.000238

GnomAD4 genome AF: 0.00155 AC: 219 AN: 141670 Hom.: 1 Cov.: 0 AF XY: 0.00150 AC XY: 103 AN XY: 68672

Gnomad4 AFR AF: 0.00473

Gnomad4 AMR AF: 0.00106

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00331

Gnomad4 SAS AF: 0.000919

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000616

Gnomad4 OTH AF: 0.000512

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;