3-47101597-AGTGTGTGTGTGTGTGTGTGTGTGT-AGTGTGTGTGTGTGTGTGTGTGTGTGTGTGT

Variant names:

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

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_4918-43dupACACAC variant causes a intron change involving the alteration of a non-conserved nucleotide. 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 0.0055 (3 hom., cov: 0)
  • Exomes 𝑓: 0.0022 (1 hom.)
• Consequence: SETD2 NM_014159.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.533
• 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 = 0.00545 (772/141648) while in subpopulation AFR AF = 0.00792 (300/37866). AF 95% confidence interval is 0.00719. There are 3 homozygotes in GnomAd4. There are 349 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High AC in GnomAd4 at 772 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_4918-43dupACACAC		intron	N/A	NP_054878.5
	SETD2	NM_001349370.3		c.4786-48_4786-43dupACACAC		intron	N/A	NP_001336299.1
	SETD2	NR_146158.3		n.5107-48_5107-43dupACACAC		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SETD2	ENST00000409792.4	TSL:5 MANE Select	c.4918-43_4918-42insACACAC		intron	N/A	ENSP00000386759.3
	SETD2	ENST00000330022.11	TSL:1	n.*641-43_*641-42insACACAC		intron	N/A	ENSP00000332415.7
	SETD2	ENST00000638947.2	TSL:5	c.4786-43_4786-42insACACAC		intron	N/A	ENSP00000491413.2

Frequencies

GnomAD3 genomes AF: 0.00544 AC: 770 AN: 141550 Hom.: 3 Cov.: 0

Gnomad AFR AF: 0.00789

Gnomad AMI AF: 0.00344

Gnomad AMR AF: 0.00476

Gnomad ASJ AF: 0.00298

Gnomad EAS AF: 0.00351

Gnomad SAS AF: 0.00550

Gnomad FIN AF: 0.000219

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00518

Gnomad OTH AF: 0.00673

GnomAD2 exomes AF: 0.00277 AC: 338 AN: 122034 AF XY: 0.00270

Gnomad AFR exome AF: 0.00269

Gnomad AMR exome AF: 0.00299

Gnomad ASJ exome AF: 0.00155

Gnomad EAS exome AF: 0.00239

Gnomad FIN exome AF: 0.000480

Gnomad NFE exome AF: 0.00335

Gnomad OTH exome AF: 0.00289

GnomAD4 exome AF: 0.00222 AC: 1317 AN: 592254 Hom.: 1 Cov.: 0 AF XY: 0.00231 AC XY: 730 AN XY: 315608

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

African (AFR) AF: 0.00185 AC: 27 AN: 14570

American (AMR) AF: 0.00235 AC: 70 AN: 29776

Ashkenazi Jewish (ASJ) AF: 0.00150 AC: 24 AN: 15966

East Asian (EAS) AF: 0.00203 AC: 64 AN: 31498

South Asian (SAS) AF: 0.00207 AC: 106 AN: 51184

European-Finnish (FIN) AF: 0.000777 AC: 35 AN: 45062

Middle Eastern (MID) AF: 0.00164 AC: 5 AN: 3046

European-Non Finnish (NFE) AF: 0.00240 AC: 893 AN: 371720

Other (OTH) AF: 0.00316 AC: 93 AN: 29432

⚠️ 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: 0.00545 AC: 772 AN: 141648 Hom.: 3 Cov.: 0 AF XY: 0.00508 AC XY: 349 AN XY: 68662

African (AFR) AF: 0.00792 AC: 300 AN: 37866

American (AMR) AF: 0.00475 AC: 67 AN: 14100

Ashkenazi Jewish (ASJ) AF: 0.00298 AC: 10 AN: 3360

East Asian (EAS) AF: 0.00352 AC: 17 AN: 4828

South Asian (SAS) AF: 0.00551 AC: 24 AN: 4352

European-Finnish (FIN) AF: 0.000219 AC: 2 AN: 9132

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

European-Non Finnish (NFE) AF: 0.00518 AC: 336 AN: 64904

Other (OTH) AF: 0.00666 AC: 13 AN: 1952

Alfa AF: 0.00183 Hom.: 313

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.53
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;