rs541943893

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 8P and 5B. PVS1BS1_SupportingBS2

The NM_014159.7(SETD2):c.19C>T(p.Gln7*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000632 in 1,313,794 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00024 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000040 ( 0 hom. )

Consequence

SETD2
NM_014159.7 stop_gained

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:6B:2

Conservation

PhyloP100: 1.30

Publications

4 publications found

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:

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

KIF9-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 57 pathogenic variants in the truncated region.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000243 (37/151988) while in subpopulation AMR AF = 0.00229 (35/15264). AF 95% confidence interval is 0.00169. There are 0 homozygotes in GnomAd4. There are 25 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 37 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SETD2	NM_014159.7 link	c.19C>T	p.Gln7*	stop_gained	Exon 1 of 21	ENST00000409792.4	NP_054878.5	Q9BYW2-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SETD2	ENST00000409792.4 link	c.19C>T	p.Gln7*	stop_gained	Exon 1 of 21	5	NM_014159.7	ENSP00000386759.3		Q9BYW2-1

Frequencies

GnomAD3 genomes

AF:

0.000244

AC:

AN:

151880

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00230

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:

0.00

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.0000319

AC:

AN:

94066

AF XY:

0.0000192

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000353

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000396

AC:

AN:

1161806

Hom.:

Cov.:

AF XY:

0.0000268

AC XY:

AN XY:

559744

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

24624

American (AMR)

AF:

0.00218

AC:

AN:

16500

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

15218

East Asian (EAS)

AF:

0.00

AC:

AN:

29910

South Asian (SAS)

AF:

0.00

AC:

AN:

28006

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38796

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4620

European-Non Finnish (NFE)

AF:

0.00000209

AC:

AN:

958070

Other (OTH)

AF:

0.000174

AC:

AN:

46062

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000243

AC:

AN:

151988

Hom.:

Cov.:

AF XY:

0.000336

AC XY:

AN XY:

74330

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41536

American (AMR)

AF:

0.00229

AC:

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10510

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67896

Other (OTH)

AF:

0.000473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.000302

ExAC

AF:

0.0000434

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:6Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Luscan-Lumish syndrome

Pathogenic:1Uncertain:2Benign:1

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 18, 2024

Servicio de Genética Del Instituto Nacional de Salud Del Niño, Ministerio de Salud

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant NM_014159.7:c.19C>T (p.Gln7)* introduces a premature stop codon at codon 7, likely resulting in a truncated protein or nonsense-mediated decay (NMD). One research study classified this variant as likely pathogenic based on the predicted loss-of-function effect -

Sep 12, 2022

New York Genome Center

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 02, 2018

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been reported in one patient (12736.p1) with autism spectrum disorder and it was inherited from the patient's mother [PMID: 23160955] -

not provided

Uncertain:2

Oct 29, 2024

Athena Diagnostics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 21, 2020

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:1

Jun 10, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: SETD2 c.19C>T (p.Gln7X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay. Pathogenic loss-of-function variants in SETD2 have been reported in the literature (PMID: 26084711, 24852293). However, there is an in-frame ATG codon (at Met 12) downstream from the variant of interest, with an appropriate context (i.e. Kozak consensus) for translational initiation that could generate an N-terminally truncated protein product with the loss of 11 N-terminal amino acids, and no pathogenic variants from the truncated region have been reported. The variant allele was found at a frequency of 3.2e-05 in 94066 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance (gnomAD v2). A total of 83 heterozygotes of this variant have been reported in the gnomAD v4 database. c.19C>T has been reported in the literature in an individual affected with autism spectrum disorder (ASD), however, this patient had normal nonverbal intelligence (with no information on head circumference), and also was noted to carry a de novo 16p11.2 duplication (ORoak_2012). c.19C>T has also been observed in at-least 4 individuals affected with Luscan-Lumish Syndrome and a patient with pediatric cancer (Parra_2023, Zhang_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Luscan-Lumish Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 26084711, 23160955, 37372360, 30419952, 26580448, 29681085). ClinVar contains an entry for this variant (Variation ID: 521678). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Inborn genetic diseases

Uncertain:1

Jun 08, 2016

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

SETD2-related disorder

Benign:1

Jan 19, 2024

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.45

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

0.69

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Benign

0.19

PhyloP100

1.3

Vest4

0.31

GERP RS

3.0

PromoterAI

-0.0096

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.1

Mutation Taster

=13/187

disease causing (fs/PTC)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over