rs1553707534

Variant names:

• chr3-47163899-G-A
• rs1553707534
• NM_014159.7:c.26C>T

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.26C>T​(p.Pro9Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000172 in 1,164,372 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000017 (0 hom.)
• Consequence: SETD2 NM_014159.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.46
• 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]

KIF9-AS1 (HGNC:26822): (KIF9 antisense RNA 1)

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 (MetaRNN=0.21075276).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SETD2	NM_014159.7	MANE Select	c.26C>T	p.Pro9Leu	missense	Exon 1 of 21	NP_054878.5
	SETD2	NM_001349370.3		c.-91C>T		5_prime_UTR	Exon 1 of 20	NP_001336299.1
	SETD2	NR_146158.3		n.215C>T		non_coding_transcript_exon	Exon 1 of 22

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SETD2	ENST00000409792.4	TSL:5 MANE Select	c.26C>T	p.Pro9Leu	missense	Exon 1 of 21	ENSP00000386759.3
	SETD2	ENST00000952253.1		c.26C>T	p.Pro9Leu	missense	Exon 1 of 20	ENSP00000622312.1
	SETD2	ENST00000893753.1		c.26C>T	p.Pro9Leu	missense	Exon 1 of 19	ENSP00000563812.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000172 AC: 2 AN: 1164372 Hom.: 0 Cov.: 30 AF XY: 0.00000178 AC XY: 1 AN XY: 561284

African (AFR) AF: 0.00 AC: 0 AN: 24654

American (AMR) AF: 0.0000597 AC: 1 AN: 16738

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15318

East Asian (EAS) AF: 0.00 AC: 0 AN: 30038

South Asian (SAS) AF: 0.00 AC: 0 AN: 28322

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39036

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4628

European-Non Finnish (NFE) AF: 0.00000104 AC: 1 AN: 959440

Other (OTH) AF: 0.00 AC: 0 AN: 46198

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Luscan-Lumish syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.093	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.071	T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.62	T
M_CAP	Pathogenic	0.84	D
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.46	T
MutationAssessor	Benign	0.34	N
PhyloP100		1.5
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-0.54	N
REVEL	Uncertain	0.30
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.0020	B
Vest4		0.28
MVP		0.29
MPC		0.28
ClinPred		0.53	D
GERP RS		2.6
PromoterAI		0.00060	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.6
Varity_R		0.17
gMVP		0.13
Mutation Taster		=88/12	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: rs1553707534; hg19: chr3-47205389;