rs11717033

Variant names:

• chr3-47126729-T-C
• rs11717033
• NM_014159.7:c.72-66A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_014159.7(SETD2):​c.72-66A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0398 in 927,100 control chromosomes in the GnomAD database, including 935 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.030 (95 hom., cov: 32)
  • Exomes 𝑓: 0.042 (840 hom.)
• Consequence: SETD2 NM_014159.7 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.247
• Publications: 6 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, STRONG Submitted by: PanelApp Australia, ClinGen
• Rabin-Pappas syndrome

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• SETD2-related microcephaly-severe intellectual disability-multiple congenital anomalies syndrome

  Inheritance: AD Classification: STRONG Submitted by: ClinGen, PanelApp Australia
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 3-47126729-T-C is Benign according to our data. Variant chr3-47126729-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 1187337.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0587 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SETD2	NM_014159.7	MANE Select	c.72-66A>G		intron	N/A	NP_054878.5
	SETD2	NM_001349370.3		c.-45-2181A>G		intron	N/A	NP_001336299.1	A0A1W2PPX9
	SETD2	NR_146158.3		n.261-66A>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SETD2	ENST00000409792.4	TSL:5 MANE Select	c.72-66A>G		intron	N/A	ENSP00000386759.3	Q9BYW2-1
	SETD2	ENST00000952253.1		c.72-66A>G		intron	N/A	ENSP00000622312.1
	SETD2	ENST00000638947.2	TSL:5	c.-45-2181A>G		intron	N/A	ENSP00000491413.2	A0A1W2PPX9

Frequencies

GnomAD3 genomes AF: 0.0303 AC: 4604 AN: 152190 Hom.: 96 Cov.: 32

Gnomad AFR AF: 0.00929

Gnomad AMI AF: 0.0351

Gnomad AMR AF: 0.0201

Gnomad ASJ AF: 0.0812

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.0515

Gnomad FIN AF: 0.0133

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0461

Gnomad OTH AF: 0.0254

GnomAD4 exome AF: 0.0417 AC: 32304 AN: 774792 Hom.: 840 AF XY: 0.0424 AC XY: 17160 AN XY: 404278

African (AFR) AF: 0.00750 AC: 142 AN: 18942

American (AMR) AF: 0.0166 AC: 476 AN: 28638

Ashkenazi Jewish (ASJ) AF: 0.0762 AC: 1537 AN: 20174

East Asian (EAS) AF: 0.0000305 AC: 1 AN: 32760

South Asian (SAS) AF: 0.0482 AC: 3085 AN: 64052

European-Finnish (FIN) AF: 0.0170 AC: 656 AN: 38652

Middle Eastern (MID) AF: 0.0652 AC: 261 AN: 4006

European-Non Finnish (NFE) AF: 0.0465 AC: 24688 AN: 530536

Other (OTH) AF: 0.0394 AC: 1458 AN: 37032

GnomAD4 genome AF: 0.0302 AC: 4603 AN: 152308 Hom.: 95 Cov.: 32 AF XY: 0.0285 AC XY: 2124 AN XY: 74492

African (AFR) AF: 0.00924 AC: 384 AN: 41578

American (AMR) AF: 0.0201 AC: 307 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0812 AC: 282 AN: 3472

East Asian (EAS) AF: 0.000579 AC: 3 AN: 5182

South Asian (SAS) AF: 0.0518 AC: 250 AN: 4830

European-Finnish (FIN) AF: 0.0133 AC: 141 AN: 10614

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.0461 AC: 3136 AN: 68016

Other (OTH) AF: 0.0256 AC: 54 AN: 2106

Alfa AF: 0.0444 Hom.: 223

Bravo AF: 0.0292

Asia WGS AF: 0.0180 AC: 63 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.63
DANN	Benign	0.53
PhyloP100		-0.25
Mutation Taster		=100/0	polymorphism

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: rs11717033; hg19: chr3-47168219;