3-47101597-AGTGTGTGTGTGTGTGTGTGTGTGT-AGTGT

Variant names:

• chr3-47101597-AGTGTGTGTGTGTGTGTGTGT-A
• rs61571386
• NM_014159.7:c.4918-62_4918-43delACACACACACACACACACAC

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_014159.7(SETD2):​c.4918-62_4918-43delACACACACACACACACACAC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 592,440 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. 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: 0.000012 (0 hom.)
• Consequence: SETD2 NM_014159.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.26
• Publications: 1 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: G2P, Labcorp Genetics (formerly Invitae), 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: Labcorp Genetics (formerly Invitae), G2P, 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: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 7 AD gene.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SETD2	NM_014159.7	MANE Select	c.4918-62_4918-43delACACACACACACACACACAC		intron	N/A	NP_054878.5
	SETD2	NM_001349370.3		c.4786-62_4786-43delACACACACACACACACACAC		intron	N/A	NP_001336299.1
	SETD2	NR_146158.3		n.5107-62_5107-43delACACACACACACACACACAC		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SETD2	ENST00000409792.4	TSL:5 MANE Select	c.4918-62_4918-43delACACACACACACACACACAC		intron	N/A	ENSP00000386759.3
	SETD2	ENST00000330022.11	TSL:1	n.*641-62_*641-43delACACACACACACACACACAC		intron	N/A	ENSP00000332415.7
	SETD2	ENST00000638947.2	TSL:5	c.4786-62_4786-43delACACACACACACACACACAC		intron	N/A	ENSP00000491413.2

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome AF: 0.0000118 AC: 7 AN: 592440 Hom.: 0 AF XY: 0.00000950 AC XY: 3 AN XY: 315702

African (AFR) AF: 0.0000686 AC: 1 AN: 14576

American (AMR) AF: 0.00 AC: 0 AN: 29782

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15974

East Asian (EAS) AF: 0.00 AC: 0 AN: 31512

South Asian (SAS) AF: 0.0000195 AC: 1 AN: 51192

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45070

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3048

European-Non Finnish (NFE) AF: 0.0000134 AC: 5 AN: 371844

Other (OTH) AF: 0.00 AC: 0 AN: 29442

GnomAD4 genome Cov.: 0

Alfa AF: 0.00 Hom.: 313

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.3
BranchPoint Hunter		4.0

Splicing

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

Other links and lift over

dbSNP: rs61571386; hg19: chr3-47143087;