3-47037660-A-C

Variant names:

• chr3-47037660-A-C
• rs369951554
• NM_014159.7:c.7350+6T>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014159.7(SETD2):​c.7350+6T>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000207 in 1,450,478 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SETD2 NM_014159.7 splice_region, intron
• Scores: Splicing: ADA: 0.7866
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.97
• 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 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SETD2	NM_014159.7	MANE Select	c.7350+6T>G		splice_region intron	N/A	NP_054878.5
	SETD2	NM_001349370.3		c.7218+6T>G		splice_region intron	N/A	NP_001336299.1
	SETD2	NR_146158.3		n.7707+6T>G		splice_region intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SETD2	ENST00000409792.4	TSL:5 MANE Select	c.7350+6T>G		splice_region intron	N/A	ENSP00000386759.3
	SETD2	ENST00000330022.11	TSL:1	n.*3073+6T>G		splice_region intron	N/A	ENSP00000332415.7
	SETD2	ENST00000638947.2	TSL:5	c.7218+6T>G		splice_region intron	N/A	ENSP00000491413.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000207 AC: 3 AN: 1450478 Hom.: 0 Cov.: 29 AF XY: 0.00000415 AC XY: 3 AN XY: 722212

African (AFR) AF: 0.00 AC: 0 AN: 33238

American (AMR) AF: 0.00 AC: 0 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26036

East Asian (EAS) AF: 0.00 AC: 0 AN: 39602

South Asian (SAS) AF: 0.00 AC: 0 AN: 86030

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53296

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 0.00000272 AC: 3 AN: 1101886

Other (OTH) AF: 0.00 AC: 0 AN: 59950

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	19
DANN	Benign	0.89
PhyloP100		2.0

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.79
dbscSNV1_RF	Benign	0.50
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: rs369951554; hg19: chr3-47079150;