NM_014159.7:c.6110-26dupA

Variant names:

• chr3-47062371-G-GT
• rs10589946
• NM_014159.7:c.6110-26dupA

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_014159.7(SETD2):​c.6110-26dupA variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 0)
  • Exomes 𝑓: 0.033 (0 hom.)
• Consequence: SETD2 NM_014159.7 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.577
• Publications: 3 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 -10 ACMG points.

• BP6: Variant 3-47062371-G-GT is Benign according to our data. Variant chr3-47062371-G-GT is described in ClinVar as Likely_benign. ClinVar VariationId is 1191604.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00131 (192/146764) while in subpopulation NFE AF = 0.00161 (107/66278). AF 95% confidence interval is 0.00137. There are 0 homozygotes in GnomAd4. There are 88 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High AC in GnomAd4 at 192 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.6110-26dupA		intron	N/A	NP_054878.5
	SETD2	NM_001349370.3		c.5978-26dupA		intron	N/A	NP_001336299.1	A0A1W2PPX9
	SETD2	NR_146158.3		n.6467-26dupA		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SETD2	ENST00000409792.4	TSL:5 MANE Select	c.6110-26_6110-25insA		intron	N/A	ENSP00000386759.3	Q9BYW2-1
	SETD2	ENST00000330022.11	TSL:1	n.*1833-26_*1833-25insA		intron	N/A	ENSP00000332415.7	H7BXT4
	SETD2	ENST00000952253.1		c.6032-26_6032-25insA		intron	N/A	ENSP00000622312.1

Frequencies

GnomAD3 genomes AF: 0.00131 AC: 192 AN: 146712 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000971

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00107

Gnomad ASJ AF: 0.000880

Gnomad EAS AF: 0.000790

Gnomad SAS AF: 0.000864

Gnomad FIN AF: 0.00188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00161

Gnomad OTH AF: 0.000987

GnomAD2 exomes AF: 0.0156 AC: 2307 AN: 147998 AF XY: 0.0160

Gnomad AFR exome AF: 0.00616

Gnomad AMR exome AF: 0.0112

Gnomad ASJ exome AF: 0.0235

Gnomad EAS exome AF: 0.0143

Gnomad FIN exome AF: 0.0127

Gnomad NFE exome AF: 0.0160

Gnomad OTH exome AF: 0.0200

GnomAD4 exome AF: 0.0326 AC: 38926 AN: 1194550 Hom.: 0 Cov.: 0 AF XY: 0.0325 AC XY: 19271 AN XY: 592128

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0130 AC: 333 AN: 25532

American (AMR) AF: 0.0142 AC: 380 AN: 26772

Ashkenazi Jewish (ASJ) AF: 0.0332 AC: 643 AN: 19354

East Asian (EAS) AF: 0.0161 AC: 559 AN: 34754

South Asian (SAS) AF: 0.0347 AC: 2219 AN: 63980

European-Finnish (FIN) AF: 0.0217 AC: 963 AN: 44416

Middle Eastern (MID) AF: 0.0346 AC: 162 AN: 4680

European-Non Finnish (NFE) AF: 0.0347 AC: 32094 AN: 925884

Other (OTH) AF: 0.0320 AC: 1573 AN: 49178

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00131 AC: 192 AN: 146764 Hom.: 0 Cov.: 0 AF XY: 0.00123 AC XY: 88 AN XY: 71386

African (AFR) AF: 0.000969 AC: 39 AN: 40246

American (AMR) AF: 0.00107 AC: 16 AN: 14906

Ashkenazi Jewish (ASJ) AF: 0.000880 AC: 3 AN: 3410

East Asian (EAS) AF: 0.000792 AC: 4 AN: 5052

South Asian (SAS) AF: 0.000868 AC: 4 AN: 4610

European-Finnish (FIN) AF: 0.00188 AC: 17 AN: 9062

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 282

European-Non Finnish (NFE) AF: 0.00161 AC: 107 AN: 66278

Other (OTH) AF: 0.000979 AC: 2 AN: 2042

Alfa AF: 0.000162 Hom.: 890

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.58
BranchPoint Hunter		1.0
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs10589946; hg19: chr3-47103861;