NM_014159.7:c.4918-44_4918-43dupAC

Variant names:

• chr3-47101597-A-AGT
• rs61571386
• NM_014159.7:c.4918-44_4918-43dupAC

Variant summary

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

The NM_014159.7(SETD2):​c.4918-44_4918-43dupAC variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.28 (5080 hom., cov: 0)
  • Exomes 𝑓: 0.12 (236 hom.)
• Consequence: SETD2 NM_014159.7 intron
• Clinical Significance: 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-AGT is Benign according to our data. Variant chr3-47101597-A-AGT is described in ClinVar as Benign. ClinVar VariationId is 1230666.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.311 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.4918-44_4918-43dupAC		intron	N/A	NP_054878.5
	SETD2	NM_001349370.3		c.4786-44_4786-43dupAC		intron	N/A	NP_001336299.1
	SETD2	NR_146158.3		n.5107-44_5107-43dupAC		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_4918-42insAC		intron	N/A	ENSP00000386759.3
	SETD2	ENST00000330022.11	TSL:1	n.*641-43_*641-42insAC		intron	N/A	ENSP00000332415.7
	SETD2	ENST00000638947.2	TSL:5	c.4786-43_4786-42insAC		intron	N/A	ENSP00000491413.2

Frequencies

GnomAD3 genomes AF: 0.278 AC: 39243 AN: 141348 Hom.: 5074 Cov.: 0

Gnomad AFR AF: 0.316

Gnomad AMI AF: 0.338

Gnomad AMR AF: 0.236

Gnomad ASJ AF: 0.309

Gnomad EAS AF: 0.199

Gnomad SAS AF: 0.194

Gnomad FIN AF: 0.254

Gnomad MID AF: 0.303

Gnomad NFE AF: 0.277

Gnomad OTH AF: 0.276

GnomAD2 exomes AF: 0.145 AC: 17743 AN: 122034 AF XY: 0.143

Gnomad AFR exome AF: 0.166

Gnomad AMR exome AF: 0.106

Gnomad ASJ exome AF: 0.152

Gnomad EAS exome AF: 0.127

Gnomad FIN exome AF: 0.172

Gnomad NFE exome AF: 0.157

Gnomad OTH exome AF: 0.141

GnomAD4 exome AF: 0.118 AC: 69534 AN: 589510 Hom.: 236 Cov.: 0 AF XY: 0.119 AC XY: 37384 AN XY: 314140

African (AFR) AF: 0.164 AC: 2363 AN: 14448

American (AMR) AF: 0.0978 AC: 2898 AN: 29630

Ashkenazi Jewish (ASJ) AF: 0.159 AC: 2520 AN: 15872

East Asian (EAS) AF: 0.115 AC: 3613 AN: 31294

South Asian (SAS) AF: 0.0755 AC: 3852 AN: 51022

European-Finnish (FIN) AF: 0.167 AC: 7457 AN: 44760

Middle Eastern (MID) AF: 0.160 AC: 485 AN: 3034

European-Non Finnish (NFE) AF: 0.114 AC: 42308 AN: 370204

Other (OTH) AF: 0.138 AC: 4038 AN: 29246

GnomAD4 genome AF: 0.278 AC: 39288 AN: 141446 Hom.: 5080 Cov.: 0 AF XY: 0.273 AC XY: 18687 AN XY: 68550

African (AFR) AF: 0.316 AC: 11947 AN: 37804

American (AMR) AF: 0.236 AC: 3329 AN: 14082

Ashkenazi Jewish (ASJ) AF: 0.309 AC: 1038 AN: 3354

East Asian (EAS) AF: 0.199 AC: 961 AN: 4820

South Asian (SAS) AF: 0.194 AC: 845 AN: 4348

European-Finnish (FIN) AF: 0.254 AC: 2309 AN: 9106

Middle Eastern (MID) AF: 0.305 AC: 86 AN: 282

European-Non Finnish (NFE) AF: 0.277 AC: 17937 AN: 64830

Other (OTH) AF: 0.278 AC: 541 AN: 1948

Alfa AF: 0.158 Hom.: 313

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Aug 21, 2019

GeneDx

Significance: 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;