3-47062371-GTTTTTTT-GTTTTT

Variant names:

• chr3-47062371-GTT-G
• rs10589946
• NM_014159.7:c.6110-27_6110-26delAA

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.6110-27_6110-26delAA 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 0.65 (30949 hom., cov: 0)
  • Exomes 𝑓: 0.50 (91665 hom.)
  • Failed GnomAD Quality Control
• Consequence: SETD2 NM_014159.7 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.247
• 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 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 3-47062371-GTT-G is Benign according to our data. Variant chr3-47062371-GTT-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 436678.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.738 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SETD2	NM_014159.7	c.6110-27_6110-26delAA		intron_variant	Intron 13 of 20	ENST00000409792.4	NP_054878.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SETD2	ENST00000409792.4	c.6110-27_6110-26delAA		intron_variant	Intron 13 of 20	5	NM_014159.7	ENSP00000386759.3

Frequencies

GnomAD3 genomes AF: 0.651 AC: 95392 AN: 146624 Hom.: 30910 Cov.: 0

Gnomad AFR AF: 0.744

Gnomad AMI AF: 0.438

Gnomad AMR AF: 0.666

Gnomad ASJ AF: 0.591

Gnomad EAS AF: 0.688

Gnomad SAS AF: 0.609

Gnomad FIN AF: 0.634

Gnomad MID AF: 0.517

Gnomad NFE AF: 0.600

Gnomad OTH AF: 0.625

GnomAD2 exomes AF: 0.593 AC: 87781 AN: 147998 AF XY: 0.584

Gnomad AFR exome AF: 0.674

Gnomad AMR exome AF: 0.701

Gnomad ASJ exome AF: 0.536

Gnomad EAS exome AF: 0.635

Gnomad FIN exome AF: 0.596

Gnomad NFE exome AF: 0.563

Gnomad OTH exome AF: 0.570

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.497 AC: 603584 AN: 1214838 Hom.: 91665 AF XY: 0.496 AC XY: 298751 AN XY: 602492

African (AFR) AF: 0.575 AC: 14784 AN: 25696

American (AMR) AF: 0.647 AC: 17504 AN: 27070

Ashkenazi Jewish (ASJ) AF: 0.491 AC: 9747 AN: 19850

East Asian (EAS) AF: 0.602 AC: 21269 AN: 35308

South Asian (SAS) AF: 0.494 AC: 32059 AN: 64912

European-Finnish (FIN) AF: 0.528 AC: 23917 AN: 45338

Middle Eastern (MID) AF: 0.496 AC: 2368 AN: 4774

European-Non Finnish (NFE) AF: 0.485 AC: 456922 AN: 941748

Other (OTH) AF: 0.499 AC: 25014 AN: 50142

GnomAD4 genome AF: 0.651 AC: 95462 AN: 146674 Hom.: 30949 Cov.: 0 AF XY: 0.649 AC XY: 46319 AN XY: 71330

African (AFR) AF: 0.745 AC: 29945 AN: 40210

American (AMR) AF: 0.666 AC: 9920 AN: 14900

Ashkenazi Jewish (ASJ) AF: 0.591 AC: 2017 AN: 3410

East Asian (EAS) AF: 0.689 AC: 3480 AN: 5050

South Asian (SAS) AF: 0.610 AC: 2805 AN: 4598

European-Finnish (FIN) AF: 0.634 AC: 5746 AN: 9058

Middle Eastern (MID) AF: 0.511 AC: 143 AN: 280

European-Non Finnish (NFE) AF: 0.600 AC: 39743 AN: 66250

Other (OTH) AF: 0.626 AC: 1279 AN: 2042

Alfa AF: 0.448 Hom.: 890

Bravo AF: 0.654

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

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

- -

Luscan-Lumish syndrome Benign:1

Mar 15, 2022

Genome-Nilou Lab

Significance: 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 v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.25
BranchPoint Hunter		1.0
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: rs10589946; hg19: chr3-47103861; COSMIC: COSV104633396;