NM_014159.7:c.6110-30_6110-26delAAAAA

Variant names:

• chr3-47062371-GTTTTT-G
• rs10589946
• NM_014159.7:c.6110-30_6110-26delAAAAA

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_014159.7(SETD2):​c.6110-30_6110-26delAAAAA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000164 in 1,219,822 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: not found (cov: 0)
  • Exomes 𝑓: 0.0000016 (0 hom.)
• Consequence: SETD2 NM_014159.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.90
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• Luscan-Lumish syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• SETD2-related neurodevelopmental disorder without or with macrocephaly/overgrowth

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• Rabin-Pappas syndrome

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• SETD2-related microcephaly-severe intellectual disability-multiple congenital anomalies syndrome

  Inheritance: AD Classification: STRONG Submitted by: ClinGen
• Sotos syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• intellectual developmental disorder, autosomal dominant 70

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014159.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SETD2	NM_014159.7	MANE Select	c.6110-30_6110-26delAAAAA		intron	N/A	NP_054878.5
	SETD2	NM_001349370.3		c.5978-30_5978-26delAAAAA		intron	N/A	NP_001336299.1	A0A1W2PPX9
	SETD2	NR_146158.3		n.6467-30_6467-26delAAAAA		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SETD2	ENST00000409792.4	TSL:5 MANE Select	c.6110-30_6110-26delAAAAA		intron	N/A	ENSP00000386759.3	Q9BYW2-1
	SETD2	ENST00000330022.11	TSL:1	n.*1833-30_*1833-26delAAAAA		intron	N/A	ENSP00000332415.7	H7BXT4
	SETD2	ENST00000952253.1		c.6032-30_6032-26delAAAAA		intron	N/A	ENSP00000622312.1

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome AF: 0.00000164 AC: 2 AN: 1219822 Hom.: 0 AF XY: 0.00000165 AC XY: 1 AN XY: 604924

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 25788

American (AMR) AF: 0.00 AC: 0 AN: 27124

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19922

East Asian (EAS) AF: 0.00 AC: 0 AN: 35366

South Asian (SAS) AF: 0.00 AC: 0 AN: 65202

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45448

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4788

European-Non Finnish (NFE) AF: 0.00000211 AC: 2 AN: 945862

Other (OTH) AF: 0.00 AC: 0 AN: 50322

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.9
BranchPoint Hunter		1.0

Splicing

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

Other links and lift over

dbSNP: rs10589946; hg19: chr3-47103861;