rs564020755

chr3-47123293-C-Achr3-47123293-C-Gchr3-47123293-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_014159.7(SETD2):c.1343G>T(p.Arg448Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R448Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SETD2 NM_014159.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.61

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, SETD2
• BP4: Computational evidence support a benign effect (MetaRNN=0.35150206).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SETD2	NM_014159.7	c.1343G>T	p.Arg448Leu	missense_variant	3/21	ENST00000409792.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SETD2	ENST00000409792.4	c.1343G>T	p.Arg448Leu	missense_variant	3/21	5	NM_014159.7	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Uncertain	0.049	T
BayesDel_noAF	Benign	-0.17
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.39	T;T
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.35	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-2.3	N;D
REVEL	Benign	0.28
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0030	D;.
Polyphen		1.0	D;.
Vest4		0.43
MutPred		0.25		Gain of glycosylation at T451 (P = 2e-04);.;
MVP		0.35
MPC		1.0
ClinPred		0.95	D
GERP RS		5.0
Varity_R		0.34
gMVP		0.29

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-47164783; COSMIC: COSV100338044; COSMIC: COSV100338044;