3-47101597-AGTGTGTGTGTGTGTGTGTGTGTGT-AGTGTGTGTGTGTGTGTGTGTGTGTGTGT

Variant names:

• chr3-47101597-A-AGTGT
• rs61571386
• NM_014159.7:c.4918-46_4918-43dupACAC

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_014159.7(SETD2):​c.4918-46_4918-43dupACAC variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.031 (61 hom., cov: 0)
  • Exomes 𝑓: 0.016 (15 hom.)
• Consequence: SETD2 NM_014159.7 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• 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 -10 ACMG points.

• BP6: Variant 3-47101597-A-AGTGT is Benign according to our data. Variant chr3-47101597-A-AGTGT is described in ClinVar as Likely_benign. ClinVar VariationId is 1220335.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0621 is higher than 0.05.

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.4918-46_4918-43dupACAC		intron	N/A	NP_054878.5
	SETD2	NM_001349370.3		c.4786-46_4786-43dupACAC		intron	N/A	NP_001336299.1
	SETD2	NR_146158.3		n.5107-46_5107-43dupACAC		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_4918-42insACAC		intron	N/A	ENSP00000386759.3
	SETD2	ENST00000330022.11	TSL:1	n.*641-43_*641-42insACAC		intron	N/A	ENSP00000332415.7
	SETD2	ENST00000638947.2	TSL:5	c.4786-43_4786-42insACAC		intron	N/A	ENSP00000491413.2

Frequencies

GnomAD3 genomes AF: 0.0306 AC: 4334 AN: 141520 Hom.: 61 Cov.: 0

Gnomad AFR AF: 0.0306

Gnomad AMI AF: 0.0103

Gnomad AMR AF: 0.0298

Gnomad ASJ AF: 0.0167

Gnomad EAS AF: 0.0682

Gnomad SAS AF: 0.0305

Gnomad FIN AF: 0.0435

Gnomad MID AF: 0.0461

Gnomad NFE AF: 0.0271

Gnomad OTH AF: 0.0311

GnomAD2 exomes AF: 0.0184 AC: 2248 AN: 122034 AF XY: 0.0180

Gnomad AFR exome AF: 0.0189

Gnomad AMR exome AF: 0.0114

Gnomad ASJ exome AF: 0.00826

Gnomad EAS exome AF: 0.0380

Gnomad FIN exome AF: 0.0278

Gnomad NFE exome AF: 0.0165

Gnomad OTH exome AF: 0.0174

GnomAD4 exome AF: 0.0157 AC: 9280 AN: 591338 Hom.: 15 Cov.: 0 AF XY: 0.0157 AC XY: 4951 AN XY: 315120

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

African (AFR) AF: 0.0196 AC: 285 AN: 14546

American (AMR) AF: 0.0105 AC: 312 AN: 29756

Ashkenazi Jewish (ASJ) AF: 0.0108 AC: 172 AN: 15948

East Asian (EAS) AF: 0.0492 AC: 1542 AN: 31372

South Asian (SAS) AF: 0.0108 AC: 551 AN: 51130

European-Finnish (FIN) AF: 0.0279 AC: 1253 AN: 44964

Middle Eastern (MID) AF: 0.0181 AC: 55 AN: 3042

European-Non Finnish (NFE) AF: 0.0126 AC: 4673 AN: 371202

Other (OTH) AF: 0.0149 AC: 437 AN: 29378

⚠️ 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: 0.0307 AC: 4342 AN: 141618 Hom.: 61 Cov.: 0 AF XY: 0.0317 AC XY: 2176 AN XY: 68644

African (AFR) AF: 0.0307 AC: 1161 AN: 37862

American (AMR) AF: 0.0298 AC: 420 AN: 14098

Ashkenazi Jewish (ASJ) AF: 0.0167 AC: 56 AN: 3356

East Asian (EAS) AF: 0.0682 AC: 329 AN: 4824

South Asian (SAS) AF: 0.0308 AC: 134 AN: 4352

European-Finnish (FIN) AF: 0.0435 AC: 397 AN: 9134

Middle Eastern (MID) AF: 0.0496 AC: 14 AN: 282

European-Non Finnish (NFE) AF: 0.0271 AC: 1759 AN: 64886

Other (OTH) AF: 0.0323 AC: 63 AN: 1952

Alfa AF: 0.0157 Hom.: 313

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Aug 10, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.53
BranchPoint Hunter		4.0
Mutation Taster		=100/0	polymorphism (auto)

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;