NM_014159.7:c.4918-56_4918-43delACACACACACACAC

Variant names:

• chr3-47101597-AGTGTGTGTGTGTGT-A
• rs61571386
• NM_014159.7:c.4918-56_4918-43delACACACACACACAC

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_014159.7(SETD2):​c.4918-56_4918-43delACACACACACACAC 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. 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 0.00012 (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
• 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: Benign. The variant received -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 the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High AC in GnomAd4 at 17 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.4918-56_4918-43delACACACACACACAC		intron	N/A	NP_054878.5
	SETD2	NM_001349370.3		c.4786-56_4786-43delACACACACACACAC		intron	N/A	NP_001336299.1
	SETD2	NR_146158.3		n.5107-56_5107-43delACACACACACACAC		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SETD2	ENST00000409792.4	TSL:5 MANE Select	c.4918-56_4918-43delACACACACACACAC		intron	N/A	ENSP00000386759.3
	SETD2	ENST00000330022.11	TSL:1	n.*641-56_*641-43delACACACACACACAC		intron	N/A	ENSP00000332415.7
	SETD2	ENST00000638947.2	TSL:5	c.4786-56_4786-43delACACACACACACAC		intron	N/A	ENSP00000491413.2

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

African (AFR) AF: 0.000137 AC: 2 AN: 14572

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

Ashkenazi Jewish (ASJ) AF: 0.0000626 AC: 1 AN: 15974

East Asian (EAS) AF: 0.0000952 AC: 3 AN: 31512

South Asian (SAS) AF: 0.00160 AC: 82 AN: 51190

European-Finnish (FIN) AF: 0.0000222 AC: 1 AN: 45070

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

European-Non Finnish (NFE) AF: 0.0000672 AC: 25 AN: 371838

Other (OTH) AF: 0.000136 AC: 4 AN: 29440

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

African (AFR) AF: 0.000106 AC: 4 AN: 37878

American (AMR) AF: 0.0000709 AC: 1 AN: 14102

Ashkenazi Jewish (ASJ) AF: 0.000298 AC: 1 AN: 3360

East Asian (EAS) AF: 0.000207 AC: 1 AN: 4830

South Asian (SAS) AF: 0.000919 AC: 4 AN: 4352

European-Finnish (FIN) AF: 0.000109 AC: 1 AN: 9134

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 282

European-Non Finnish (NFE) AF: 0.0000770 AC: 5 AN: 64908

Other (OTH) AF: 0.00 AC: 0 AN: 1952

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;