NM_014159.7:c.5444T>G

Variant names:

• chr3-47084336-A-C
• rs869025570
• NM_014159.7:c.5444T>G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_014159.7(SETD2):​c.5444T>G​(p.Leu1815Trp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SETD2 NM_014159.7 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.63

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 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.86
• PP5: Variant 3-47084336-A-C is Pathogenic according to our data. Variant chr3-47084336-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 222954.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr3-47084336-A-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SETD2	NM_014159.7	c.5444T>G	p.Leu1815Trp	missense_variant	Exon 12 of 21	ENST00000409792.4	NP_054878.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SETD2	ENST00000409792.4	c.5444T>G	p.Leu1815Trp	missense_variant	Exon 12 of 21	5	NM_014159.7	ENSP00000386759.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Luscan-Lumish syndrome Pathogenic:1

Oct 21, 2016

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Uncertain	25
DANN	Benign	0.96
DEOGEN2	Uncertain	0.70	D;.
Eigen	Pathogenic	0.68
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.86	D;D
MetaSVM	Uncertain	0.78	D
MutationAssessor	Uncertain	2.3	M;.
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-5.8	D;.
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;.
Sift4G	Uncertain	0.0030	D;.
Polyphen		1.0	D;.
Vest4		0.62
MutPred		0.39		Loss of glycosylation at T1811 (P = 0.045);.;
MVP		0.85
MPC		1.9
ClinPred		0.99	D
GERP RS		4.6
Varity_R		0.76
gMVP		0.89

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs869025570; hg19: chr3-47125826;