NM_014159.7:c.4839+332G>T

Variant names:

• chr3-47105665-C-A
• rs587777969
• NM_014159.7:c.4839+332G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_014159.7(SETD2):​c.4839+332G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000978 in 450,056 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as not provided (no stars).

• Frequency:
  • Genomes: 𝑓 0.000099 (0 hom., cov: 29)
  • Exomes 𝑓: 0.000097 (0 hom.)
• Consequence: SETD2 NM_014159.7 intron
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: -0.621
• Publications: 0 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.04).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0000988 (15/151852) while in subpopulation NFE AF = 0.000221 (15/67962). AF 95% confidence interval is 0.000135. There are 0 homozygotes in GnomAd4. There are 5 alleles in the male GnomAd4 subpopulation. Median coverage is 29. This position passed quality control check.
• BS2: High AC in GnomAd4 at 15 AD gene.

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.4839+332G>T		intron	N/A	NP_054878.5
	SETD2	NM_001349370.3		c.4707+332G>T		intron	N/A	NP_001336299.1	A0A1W2PPX9
	SETD2	NR_146158.3		n.5028+332G>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SETD2	ENST00000409792.4	TSL:5 MANE Select	c.4839+332G>T		intron	N/A	ENSP00000386759.3	Q9BYW2-1
	SETD2	ENST00000330022.11	TSL:1	n.*563-2242G>T		intron	N/A	ENSP00000332415.7	H7BXT4
	SETD2	ENST00000952253.1		c.4839+332G>T		intron	N/A	ENSP00000622312.1

Frequencies

GnomAD3 genomes AF: 0.0000988 AC: 15 AN: 151852 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000506 AC: 6 AN: 118652 AF XY: 0.0000460

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000135

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000972 AC: 29 AN: 298204 Hom.: 0 Cov.: 0 AF XY: 0.0000823 AC XY: 14 AN XY: 170170

African (AFR) AF: 0.00 AC: 0 AN: 8136

American (AMR) AF: 0.00 AC: 0 AN: 24506

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10558

East Asian (EAS) AF: 0.00 AC: 0 AN: 9162

South Asian (SAS) AF: 0.00 AC: 0 AN: 57992

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 12372

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2736

European-Non Finnish (NFE) AF: 0.000164 AC: 26 AN: 158648

Other (OTH) AF: 0.000213 AC: 3 AN: 14094

GnomAD4 genome AF: 0.0000988 AC: 15 AN: 151852 Hom.: 0 Cov.: 29 AF XY: 0.0000674 AC XY: 5 AN XY: 74176

African (AFR) AF: 0.00 AC: 0 AN: 41346

American (AMR) AF: 0.00 AC: 0 AN: 15226

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10552

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000221 AC: 15 AN: 67962

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.000139 Hom.: 0

Bravo AF: 0.0000793

ClinVar

ClinVar submissions

Significance: not provided

Revision: no classification provided

Pathogenic	VUS	Benign	Condition
-	-	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.69
DANN	Benign	0.51
PhyloP100		-0.62
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: rs587777969; hg19: chr3-47147155;