3-47116683-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP2BP4

The NM_014159.7(SETD2):​c.4526G>A​(p.Arg1509Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,270 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 not provided (no stars).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Consequence

SETD2
NM_014159.7 missense

Scores

3
8
8

Clinical Significance

not provided no classification provided O:1

Conservation

PhyloP100: 7.84
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SETD2. . Gene score misZ 3.0459 (greater than the threshold 3.09). Trascript score misZ 4.1385 (greater than threshold 3.09). GenCC has associacion of gene with SETD2-related neurodevelopmental disorder without or with macrocephaly/overgrowth, Luscan-Lumish syndrome, Rabin-Pappas syndrome, SETD2-related microcephaly-severe intellectual disability-multiple congenital anomalies syndrome, Sotos syndrome.
BP4
Computational evidence support a benign effect (MetaRNN=0.39890608).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SETD2NM_014159.7 linkuse as main transcriptc.4526G>A p.Arg1509Lys missense_variant 4/21 ENST00000409792.4 NP_054878.5

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SETD2ENST00000409792.4 linkuse as main transcriptc.4526G>A p.Arg1509Lys missense_variant 4/215 NM_014159.7 ENSP00000386759 P3Q9BYW2-1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152152
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
Cov.:
28
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152270
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
74456
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00

ClinVar

Significance: not provided
Submissions summary: Other:1
Revision: no classification provided
LINK: link

Submissions by phenotype

not specified Other:1
not provided, no classification providedreference populationITMISep 19, 2013- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.29
BayesDel_addAF
Uncertain
0.10
D
BayesDel_noAF
Benign
-0.090
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.19
T;.
Eigen
Pathogenic
0.71
Eigen_PC
Pathogenic
0.76
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Benign
0.83
T;T
M_CAP
Uncertain
0.093
D
MetaRNN
Benign
0.40
T;T
MetaSVM
Uncertain
0.044
D
MutationAssessor
Benign
1.7
L;.
MutationTaster
Benign
1.0
D
PrimateAI
Uncertain
0.69
T
PROVEAN
Benign
-1.6
N;.
REVEL
Uncertain
0.37
Sift
Uncertain
0.024
D;.
Sift4G
Uncertain
0.019
D;.
Polyphen
0.99
D;.
Vest4
0.25
MutPred
0.34
Gain of ubiquitination at R1509 (P = 0.0022);.;
MVP
0.79
MPC
2.6
ClinPred
0.98
D
GERP RS
5.9
Varity_R
0.69
gMVP
0.96

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs528393799; hg19: chr3-47158173; API