chr3-47101597-AGTGTGT-A

Variant names:

• chr3-47101597-AGTGTGT-A
• rs61571386
• NM_014159.7:c.4918-48_4918-43delACACAC

Variant summary

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

The NM_014159.7(SETD2):​c.4918-48_4918-43delACACAC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00731 in 732,570 control chromosomes in the GnomAD database, including 19 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 0.0085 (8 hom., cov: 0)
  • Exomes 𝑓: 0.0070 (11 hom.)
• Consequence: SETD2 NM_014159.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.06
• 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 afr. GnomAd4 allele frequency = 0.00848 (1201/141652) while in subpopulation AFR AF = 0.0178 (673/37872). AF 95% confidence interval is 0.0167. There are 8 homozygotes in GnomAd4. There are 589 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1201 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.4918-48_4918-43delACACAC		intron	N/A	NP_054878.5
	SETD2	NM_001349370.3		c.4786-48_4786-43delACACAC		intron	N/A	NP_001336299.1
	SETD2	NR_146158.3		n.5107-48_5107-43delACACAC		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SETD2	ENST00000409792.4	TSL:5 MANE Select	c.4918-48_4918-43delACACAC		intron	N/A	ENSP00000386759.3
	SETD2	ENST00000330022.11	TSL:1	n.*641-48_*641-43delACACAC		intron	N/A	ENSP00000332415.7
	SETD2	ENST00000638947.2	TSL:5	c.4786-48_4786-43delACACAC		intron	N/A	ENSP00000491413.2

Frequencies

GnomAD3 genomes AF: 0.00849 AC: 1202 AN: 141554 Hom.: 8 Cov.: 0

Gnomad AFR AF: 0.0178

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00995

Gnomad ASJ AF: 0.0467

Gnomad EAS AF: 0.00620

Gnomad SAS AF: 0.00780

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0197

Gnomad NFE AF: 0.00220

Gnomad OTH AF: 0.0109

GnomAD2 exomes AF: 0.0138 AC: 1682 AN: 122034 AF XY: 0.0125

Gnomad AFR exome AF: 0.0203

Gnomad AMR exome AF: 0.0369

Gnomad ASJ exome AF: 0.0423

Gnomad EAS exome AF: 0.0265

Gnomad FIN exome AF: 0.00224

Gnomad NFE exome AF: 0.00616

Gnomad OTH exome AF: 0.0127

GnomAD4 exome AF: 0.00702 AC: 4151 AN: 590918 Hom.: 11 AF XY: 0.00688 AC XY: 2167 AN XY: 314906

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

African (AFR) AF: 0.0154 AC: 224 AN: 14534

American (AMR) AF: 0.0249 AC: 740 AN: 29660

Ashkenazi Jewish (ASJ) AF: 0.0366 AC: 583 AN: 15936

East Asian (EAS) AF: 0.0173 AC: 541 AN: 31312

South Asian (SAS) AF: 0.00900 AC: 460 AN: 51084

European-Finnish (FIN) AF: 0.00222 AC: 100 AN: 44948

Middle Eastern (MID) AF: 0.0148 AC: 45 AN: 3044

European-Non Finnish (NFE) AF: 0.00323 AC: 1199 AN: 371040

Other (OTH) AF: 0.00882 AC: 259 AN: 29360

⚠️ 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 AF: 0.00848 AC: 1201 AN: 141652 Hom.: 8 Cov.: 0 AF XY: 0.00858 AC XY: 589 AN XY: 68662

African (AFR) AF: 0.0178 AC: 673 AN: 37872

American (AMR) AF: 0.00993 AC: 140 AN: 14096

Ashkenazi Jewish (ASJ) AF: 0.0467 AC: 157 AN: 3360

East Asian (EAS) AF: 0.00621 AC: 30 AN: 4828

South Asian (SAS) AF: 0.00735 AC: 32 AN: 4352

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9132

Middle Eastern (MID) AF: 0.0177 AC: 5 AN: 282

European-Non Finnish (NFE) AF: 0.00220 AC: 143 AN: 64906

Other (OTH) AF: 0.0108 AC: 21 AN: 1952

Alfa AF: 0.00780 Hom.: 313

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.1
BranchPoint Hunter		4.0
Mutation Taster		=100/0	polymorphism

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;