rs75248784

Positions:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_014159.7(SETD2):c.2543C>T(p.Ala848Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00151 in 1,613,772 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0080 ( 16 hom., cov: 32)

Exomes 𝑓: 0.00083 ( 22 hom. )

Consequence

SETD2
NM_014159.7 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7O:1

Conservation

PhyloP100: 2.14

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]

SETD2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

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=0.0052988827).

BP6

Variant 3-47122093-G-A is Benign according to our data. Variant chr3-47122093-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 135221.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-47122093-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00798 (1215/152244) while in subpopulation AFR AF= 0.0285 (1182/41540). AF 95% confidence interval is 0.0271. There are 16 homozygotes in gnomad4. There are 567 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1215 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SETD2	NM_014159.7 linkuse as main transcript	c.2543C>T	p.Ala848Val	missense_variant	3/21	ENST00000409792.4	NP_054878.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SETD2	ENST00000409792.4 linkuse as main transcript	c.2543C>T	p.Ala848Val	missense_variant	3/21	5	NM_014159.7	ENSP00000386759	P3	Q9BYW2-1

Frequencies

GnomAD3 genomes

AF:

0.00799

AC:

1216

AN:

152126

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0286

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00164

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:

0.00335

GnomAD3 exomes

AF:

0.00192

AC:

480

AN:

250458

Hom.:

AF XY:

0.00134

AC XY:

182

AN XY:

135468

show subpopulations

Gnomad AFR exome

AF:

0.0278

Gnomad AMR exome

AF:

0.000724

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000265

Gnomad OTH exome

AF:

0.000493

GnomAD4 exome

AF:

0.000831

AC:

1215

AN:

1461528

Hom.:

Cov.:

AF XY:

0.000686

AC XY:

499

AN XY:

727064

show subpopulations

Gnomad4 AFR exome

AF:

0.0324

Gnomad4 AMR exome

AF:

0.000872

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000899

Gnomad4 OTH exome

AF:

0.00132

GnomAD4 genome

AF:

0.00798

AC:

1215

AN:

152244

Hom.:

Cov.:

AF XY:

0.00762

AC XY:

567

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.0285

Gnomad4 AMR

AF:

0.00164

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:

0.00331

Alfa

AF:

0.00161

Hom.:

Bravo

AF:

0.00921

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0263

AC:

116

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00237

AC:

288

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 25, 2023	See Variant Classification Assertion Criteria. -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Apr 19, 2017	- -

not specified

Benign:2Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 08, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Oct 23, 2018	- -

Luscan-Lumish syndrome

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Mar 15, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 15, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.16

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.099

T;T

Eigen

Benign

-0.65

Eigen_PC

Benign

-0.58

FATHMM_MKL

Benign

0.33

LIST_S2

Benign

0.72

T;T

MetaRNN

Benign

0.0053

T;T

MetaSVM

Benign

-0.62

MutationAssessor

Benign

0.69

N;.

MutationTaster

Benign

1.0

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.87

N;N

REVEL

Benign

0.16

Sift

Uncertain

0.0040

D;D

Sift4G

Uncertain

0.031

D;.

Polyphen

0.0010

B;.

Vest4

0.079

MVP

0.62

MPC

0.26

ClinPred

0.010

GERP RS

2.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.061

gMVP

0.21

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over