3-47101597-AGTGT-A

Variant names:

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

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_4918-43delACAC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0408 in 726,374 control chromosomes in the GnomAD database, including 355 homozygotes. Variant has been reported in ClinVar as Benign (★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.039 (219 hom., cov: 0)
  • Exomes 𝑓: 0.041 (136 hom.)
• Consequence: SETD2 NM_014159.7 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.996
• 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-AGTGT-A is Benign according to our data. Variant chr3-47101597-AGTGT-A is described in ClinVar as Benign. ClinVar VariationId is 1292847.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.128 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_4918-43delACAC		intron	N/A	NP_054878.5
	SETD2	NM_001349370.3		c.4786-46_4786-43delACAC		intron	N/A	NP_001336299.1
	SETD2	NR_146158.3		n.5107-46_5107-43delACAC		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SETD2	ENST00000409792.4	TSL:5 MANE Select	c.4918-46_4918-43delACAC		intron	N/A	ENSP00000386759.3
	SETD2	ENST00000330022.11	TSL:1	n.*641-46_*641-43delACAC		intron	N/A	ENSP00000332415.7
	SETD2	ENST00000638947.2	TSL:5	c.4786-46_4786-43delACAC		intron	N/A	ENSP00000491413.2

Frequencies

GnomAD3 genomes AF: 0.0388 AC: 5495 AN: 141484 Hom.: 219 Cov.: 0

Gnomad AFR AF: 0.0260

Gnomad AMI AF: 0.00229

Gnomad AMR AF: 0.124

Gnomad ASJ AF: 0.0319

Gnomad EAS AF: 0.137

Gnomad SAS AF: 0.0608

Gnomad FIN AF: 0.0206

Gnomad MID AF: 0.0493

Gnomad NFE AF: 0.0228

Gnomad OTH AF: 0.0300

GnomAD2 exomes AF: 0.0693 AC: 8462 AN: 122034 AF XY: 0.0674

Gnomad AFR exome AF: 0.0535

Gnomad AMR exome AF: 0.176

Gnomad ASJ exome AF: 0.0449

Gnomad EAS exome AF: 0.126

Gnomad FIN exome AF: 0.0486

Gnomad NFE exome AF: 0.0474

Gnomad OTH exome AF: 0.0525

GnomAD4 exome AF: 0.0413 AC: 24160 AN: 584792 Hom.: 136 AF XY: 0.0414 AC XY: 12903 AN XY: 311624

African (AFR) AF: 0.0353 AC: 509 AN: 14402

American (AMR) AF: 0.124 AC: 3664 AN: 29498

Ashkenazi Jewish (ASJ) AF: 0.0387 AC: 611 AN: 15790

East Asian (EAS) AF: 0.128 AC: 3961 AN: 30916

South Asian (SAS) AF: 0.0453 AC: 2296 AN: 50702

European-Finnish (FIN) AF: 0.0396 AC: 1749 AN: 44202

Middle Eastern (MID) AF: 0.0388 AC: 117 AN: 3018

European-Non Finnish (NFE) AF: 0.0274 AC: 10067 AN: 367214

Other (OTH) AF: 0.0408 AC: 1186 AN: 29050

GnomAD4 genome AF: 0.0389 AC: 5501 AN: 141582 Hom.: 219 Cov.: 0 AF XY: 0.0421 AC XY: 2887 AN XY: 68638

African (AFR) AF: 0.0259 AC: 982 AN: 37866

American (AMR) AF: 0.124 AC: 1744 AN: 14074

Ashkenazi Jewish (ASJ) AF: 0.0319 AC: 107 AN: 3354

East Asian (EAS) AF: 0.137 AC: 662 AN: 4828

South Asian (SAS) AF: 0.0609 AC: 265 AN: 4348

European-Finnish (FIN) AF: 0.0206 AC: 188 AN: 9112

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

European-Non Finnish (NFE) AF: 0.0228 AC: 1478 AN: 64894

Other (OTH) AF: 0.0302 AC: 59 AN: 1952

Alfa AF: 0.0263 Hom.: 313

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Sep 13, 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		1.0
BranchPoint Hunter		4.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs61571386; hg19: chr3-47143087;