3-47101597-AGTGTGTGTGTGTGTGTGTGTGTGT-AGTGTGT

Variant names:

• chr3-47101597-AGTGTGTGTGTGTGTGTGT-A
• rs61571386
• NM_014159.7:c.4918-60_4918-43delACACACACACACACACAC

Variant summary

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

The NM_014159.7(SETD2):​c.4918-60_4918-43delACACACACACACACACAC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000409 in 734,010 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: 𝑓 0.0000071 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0000034 (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: Uncertain_significance. The variant received 0 ACMG points.

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.4918-60_4918-43delACACACACACACACACAC		intron	N/A	NP_054878.5
	SETD2	NM_001349370.3		c.4786-60_4786-43delACACACACACACACACAC		intron	N/A	NP_001336299.1
	SETD2	NR_146158.3		n.5107-60_5107-43delACACACACACACACACAC		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SETD2	ENST00000409792.4	TSL:5 MANE Select	c.4918-60_4918-43delACACACACACACACACAC		intron	N/A	ENSP00000386759.3
	SETD2	ENST00000330022.11	TSL:1	n.*641-60_*641-43delACACACACACACACACAC		intron	N/A	ENSP00000332415.7
	SETD2	ENST00000638947.2	TSL:5	c.4786-60_4786-43delACACACACACACACACAC		intron	N/A	ENSP00000491413.2

Frequencies

GnomAD3 genomes AF: 0.00000706 AC: 1 AN: 141572 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000154

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000338 AC: 2 AN: 592438 Hom.: 0 AF XY: 0.00000634 AC XY: 2 AN XY: 315700

⚠️ 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: 14576

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

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

East Asian (EAS) AF: 0.0000317 AC: 1 AN: 31512

South Asian (SAS) AF: 0.00 AC: 0 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: 0.00000269 AC: 1 AN: 371842

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

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000000000983081), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000706 AC: 1 AN: 141572 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 68566

African (AFR) AF: 0.00 AC: 0 AN: 37764

American (AMR) AF: 0.00 AC: 0 AN: 14082

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3360

East Asian (EAS) AF: 0.00 AC: 0 AN: 4842

South Asian (SAS) AF: 0.00 AC: 0 AN: 4360

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9134

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 304

European-Non Finnish (NFE) AF: 0.0000154 AC: 1 AN: 64922

Other (OTH) AF: 0.00 AC: 0 AN: 1932

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;