3-47121814-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_014159.7(SETD2):​c.2822A>G​(p.Lys941Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000186 in 1,613,998 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: š‘“ 0.0000066 ( 0 hom., cov: 32)
Exomes š‘“: 0.000020 ( 0 hom. )

Consequence

SETD2
NM_014159.7 missense

Scores

19

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 0.431
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 Benign. Variant got -13 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.04597774).
BP6
Variant 3-47121814-T-C is Benign according to our data. Variant chr3-47121814-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 542222.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
BS1
Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.0000198 (29/1461796) while in subpopulation NFE AF= 0.0000243 (27/1111948). AF 95% confidence interval is 0.0000166. There are 0 homozygotes in gnomad4_exome. There are 11 alleles in male gnomad4_exome subpopulation. Median coverage is 34. This position pass quality control queck.
BS2
High AC in GnomAdExome4 at 29 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SETD2NM_014159.7 linkc.2822A>G p.Lys941Arg missense_variant Exon 3 of 21 ENST00000409792.4 NP_054878.5 Q9BYW2-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SETD2ENST00000409792.4 linkc.2822A>G p.Lys941Arg missense_variant Exon 3 of 21 5 NM_014159.7 ENSP00000386759.3 Q9BYW2-1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152202
Hom.:
0
Cov.:
32
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:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251128
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135702
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000881
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000198
AC:
29
AN:
1461796
Hom.:
0
Cov.:
34
AF XY:
0.0000151
AC XY:
11
AN XY:
727196
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.0000383
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000243
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152202
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74350
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:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000113

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Luscan-Lumish syndrome Uncertain:1
Nov 30, 2021
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 941 of the SETD2 protein (p.Lys941Arg). This variant has not been reported in the literature in individuals affected with SETD2-related conditions. ClinVar contains an entry for this variant (Variation ID: 542222). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The arginine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided Benign:1
May 01, 2024
CeGaT Center for Human Genetics Tuebingen
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

SETD2: BP4 -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.060
BayesDel_addAF
Benign
-0.097
T
BayesDel_noAF
Benign
-0.38
CADD
Benign
14
DANN
Benign
0.95
DEOGEN2
Benign
0.22
T;T
Eigen
Benign
-0.82
Eigen_PC
Benign
-0.69
FATHMM_MKL
Benign
0.24
N
LIST_S2
Benign
0.70
T;T
M_CAP
Benign
0.044
D
MetaRNN
Benign
0.046
T;T
MetaSVM
Benign
-0.78
T
MutationAssessor
Benign
0.26
N;.
PrimateAI
Benign
0.29
T
PROVEAN
Benign
-0.48
N;N
REVEL
Benign
0.064
Sift
Benign
0.29
T;T
Sift4G
Benign
0.36
T;.
Polyphen
0.0
B;.
Vest4
0.027
MutPred
0.14
Loss of ubiquitination at K941 (P = 0.0017);.;
MVP
0.44
MPC
0.21
ClinPred
0.023
T
GERP RS
1.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.8
Varity_R
0.024
gMVP
0.22

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: rs1398213134; hg19: chr3-47163304; API