rs541943893

Positions:

• chr3-47163906-G-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 8P and 9B. PVS1 BP6 BS1 BS2

The NM_014159.7(SETD2):​c.19C>T​(p.Gln7Ter) 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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:2
• Conservation: PhyloP100: 1.30

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]

ACMG classification

Verdict is Likely_benign. Variant got -1 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 41 pathogenic variants in the truncated region.
• BP6: Variant 3-47163906-G-A is Benign according to our data. Variant chr3-47163906-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 521678.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=5, Likely_benign=2}.
• 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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 37 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SETD2	NM_014159.7	c.19C>T	p.Gln7Ter	stop_gained	1/21	ENST00000409792.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SETD2	ENST00000409792.4	c.19C>T	p.Gln7Ter	stop_gained	1/21	5	NM_014159.7	P3
SETD2	ENST00000691544.1	c.19C>T	p.Gln7Ter	stop_gained	1/14
SETD2	ENST00000638947.2			upstream_gene_variant		5		A2

Frequencies

GnomAD3 genomes AF: 0.000244 AC: 37 AN: 151880 Hom.: 0 Cov.: 33

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

GnomAD3 exomes AF: 0.0000319 AC: 3 AN: 94066 Hom.: 0 AF XY: 0.0000192 AC XY: 1 AN XY: 52216

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 SAS 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: 46 AN: 1161806 Hom.: 0 Cov.: 30 AF XY: 0.0000268 AC XY: 15 AN XY: 559744

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00218

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000209

Gnomad4 OTH exome AF: 0.000174

GnomAD4 genome AF: 0.000243 AC: 37 AN: 151988 Hom.: 0 Cov.: 33 AF XY: 0.000336 AC XY: 25 AN XY: 74330

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00229

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.000302

ExAC AF: 0.0000434 AC: 5

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Luscan-Lumish syndrome Uncertain:2 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 07, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 02, 2018	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] -
Uncertain significance, criteria provided, single submitter	clinical testing	New York Genome Center	Sep 12, 2022	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Sep 25, 2019

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 a second 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). The variant allele was found at a frequency of 4.8e-05 in 125046 control chromosomes (gnomAD), predominantly reported in the Latino subpopulation with a frequency of 0.00054 (i.e. 5/9314 alleles). 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 (O'Roak_2012). Therefore this report does 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. Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (1x) or uncertain significance (1x). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 08, 2016

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Dec 21, 2020

- -

SETD2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 19, 2024

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	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	36
DANN	Uncertain	1.0
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Benign	0.19	N
MutationTaster	Benign	1.0	A
Vest4		0.31
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1

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

Other links and lift over

dbSNP: rs541943893; hg19: chr3-47205396;