3-47101597-AGT-A

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_014159.7(SETD2):​c.4918-44_4918-43delAC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.143 in 720,254 control chromosomes in the GnomAD database, including 1,790 homozygotes. Variant has been reported in ClinVar as Likely benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.15 (1437 hom., cov: 0)
  • Exomes 𝑓: 0.14 (353 hom.)
• Consequence: SETD2 NM_014159.7 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• 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 -16 ACMG points.

• BP6: Variant 3-47101597-AGT-A is Benign according to our data. Variant chr3-47101597-AGT-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 436680.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.182 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_4918-43delAC		intron	N/A	NP_054878.5
	SETD2	NM_001349370.3		c.4786-44_4786-43delAC		intron	N/A	NP_001336299.1
	SETD2	NR_146158.3		n.5107-44_5107-43delAC		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SETD2	ENST00000409792.4	TSL:5 MANE Select	c.4918-44_4918-43delAC		intron	N/A	ENSP00000386759.3
	SETD2	ENST00000330022.11	TSL:1	n.*641-44_*641-43delAC		intron	N/A	ENSP00000332415.7
	SETD2	ENST00000638947.2	TSL:5	c.4786-44_4786-43delAC		intron	N/A	ENSP00000491413.2

Frequencies

GnomAD3 genomes AF: 0.148 AC: 20853 AN: 141314 Hom.: 1439 Cov.: 0

Gnomad AFR AF: 0.185

Gnomad AMI AF: 0.175

Gnomad AMR AF: 0.0885

Gnomad ASJ AF: 0.132

Gnomad EAS AF: 0.0591

Gnomad SAS AF: 0.111

Gnomad FIN AF: 0.155

Gnomad MID AF: 0.0954

Gnomad NFE AF: 0.147

Gnomad OTH AF: 0.142

GnomAD2 exomes AF: 0.186 AC: 22665 AN: 122034 AF XY: 0.192

Gnomad AFR exome AF: 0.172

Gnomad AMR exome AF: 0.113

Gnomad ASJ exome AF: 0.146

Gnomad EAS exome AF: 0.144

Gnomad FIN exome AF: 0.227

Gnomad NFE exome AF: 0.206

Gnomad OTH exome AF: 0.185

GnomAD4 exome AF: 0.142 AC: 82145 AN: 578844 Hom.: 353 AF XY: 0.144 AC XY: 44403 AN XY: 308346

African (AFR) AF: 0.146 AC: 2083 AN: 14300

American (AMR) AF: 0.0956 AC: 2808 AN: 29368

Ashkenazi Jewish (ASJ) AF: 0.152 AC: 2376 AN: 15650

East Asian (EAS) AF: 0.158 AC: 4798 AN: 30294

South Asian (SAS) AF: 0.115 AC: 5790 AN: 50516

European-Finnish (FIN) AF: 0.205 AC: 8925 AN: 43458

Middle Eastern (MID) AF: 0.124 AC: 369 AN: 2986

European-Non Finnish (NFE) AF: 0.139 AC: 50571 AN: 363612

Other (OTH) AF: 0.154 AC: 4425 AN: 28660

GnomAD4 genome AF: 0.148 AC: 20865 AN: 141410 Hom.: 1437 Cov.: 0 AF XY: 0.146 AC XY: 10015 AN XY: 68518

African (AFR) AF: 0.185 AC: 7002 AN: 37804

American (AMR) AF: 0.0884 AC: 1244 AN: 14078

Ashkenazi Jewish (ASJ) AF: 0.132 AC: 442 AN: 3356

East Asian (EAS) AF: 0.0591 AC: 285 AN: 4824

South Asian (SAS) AF: 0.112 AC: 484 AN: 4340

European-Finnish (FIN) AF: 0.155 AC: 1407 AN: 9086

Middle Eastern (MID) AF: 0.0922 AC: 26 AN: 282

European-Non Finnish (NFE) AF: 0.147 AC: 9545 AN: 64820

Other (OTH) AF: 0.143 AC: 278 AN: 1950

Alfa AF: 0.110 Hom.: 313

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Apr 29, 2016

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Aug 15, 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; COSMIC: COSV57441536; COSMIC: COSV57441536;