chr3-47062371-GTTT-G

Variant names:

• chr3-47062371-GTTT-G
• rs10589946
• NM_014159.7:c.6110-28_6110-26delAAA

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_014159.7(SETD2):​c.6110-28_6110-26delAAA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00716 in 1,344,060 control chromosomes in the GnomAD database, including 6 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.0028 (2 hom., cov: 0)
  • Exomes 𝑓: 0.0077 (4 hom.)
• Consequence: SETD2 NM_014159.7 intron
• Clinical Significance: Not reported in ClinVar
• 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 -8 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00276 (405/146738) while in subpopulation AFR AF = 0.00606 (244/40238). AF 95% confidence interval is 0.00544. There are 2 homozygotes in GnomAd4. There are 181 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High AC in GnomAd4 at 405 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SETD2	NM_014159.7	c.6110-28_6110-26delAAA		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.6110-28_6110-26delAAA		intron_variant	Intron 13 of 20	5	NM_014159.7	ENSP00000386759.3

Frequencies

GnomAD3 genomes AF: 0.00277 AC: 407 AN: 146686 Hom.: 2 Cov.: 0

Gnomad AFR AF: 0.00608

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000806

Gnomad ASJ AF: 0.00323

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00216

Gnomad FIN AF: 0.00188

Gnomad MID AF: 0.00329

Gnomad NFE AF: 0.00166

Gnomad OTH AF: 0.000987

GnomAD2 exomes AF: 0.00991 AC: 1467 AN: 147998 AF XY: 0.0100

Gnomad AFR exome AF: 0.0173

Gnomad AMR exome AF: 0.00776

Gnomad ASJ exome AF: 0.0185

Gnomad EAS exome AF: 0.00578

Gnomad FIN exome AF: 0.00738

Gnomad NFE exome AF: 0.00982

Gnomad OTH exome AF: 0.00911

GnomAD4 exome AF: 0.00770 AC: 9215 AN: 1197322 Hom.: 4 AF XY: 0.00751 AC XY: 4460 AN XY: 593878

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

African (AFR) AF: 0.0166 AC: 416 AN: 25026

American (AMR) AF: 0.00522 AC: 139 AN: 26608

Ashkenazi Jewish (ASJ) AF: 0.0109 AC: 213 AN: 19554

East Asian (EAS) AF: 0.00330 AC: 114 AN: 34528

South Asian (SAS) AF: 0.00888 AC: 568 AN: 63946

European-Finnish (FIN) AF: 0.00736 AC: 326 AN: 44312

Middle Eastern (MID) AF: 0.00551 AC: 26 AN: 4722

European-Non Finnish (NFE) AF: 0.00755 AC: 7018 AN: 929250

Other (OTH) AF: 0.00800 AC: 395 AN: 49376

⚠️ 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: 0.00276 AC: 405 AN: 146738 Hom.: 2 Cov.: 0 AF XY: 0.00254 AC XY: 181 AN XY: 71368

African (AFR) AF: 0.00606 AC: 244 AN: 40238

American (AMR) AF: 0.000805 AC: 12 AN: 14906

Ashkenazi Jewish (ASJ) AF: 0.00323 AC: 11 AN: 3410

East Asian (EAS) AF: 0.00 AC: 0 AN: 5054

South Asian (SAS) AF: 0.00195 AC: 9 AN: 4610

European-Finnish (FIN) AF: 0.00188 AC: 17 AN: 9058

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

European-Non Finnish (NFE) AF: 0.00166 AC: 110 AN: 66262

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

Alfa AF: 0.00178 Hom.: 890

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.25
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

Other links and lift over

dbSNP: rs10589946; hg19: chr3-47103861;