rs886041593

Positions:

• chr3-9453732-A-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PP3 PP5_Very_Strong

The NM_001080517.3(SETD5):​c.2347-7A>G variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: SETD5 NM_001080517.3 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.9995
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: -0.397

Genes affected

SETD5 (HGNC:25566): (SET domain containing 5) This function of this gene has yet to be determined but based on sequence similarity to other SET domain proteins it may function as a histone methyltransferase. Mutations in this gene have been associated with an autosomal dominant form of intellectual disability. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2017]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 3-9453732-A-G is Pathogenic according to our data. Variant chr3-9453732-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 280376.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-9453732-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SETD5	NM_001080517.3	c.2347-7A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000402198.7	NP_001073986.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SETD5	ENST00000402198.7	c.2347-7A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_001080517.3	ENSP00000385852	P4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Lifecell International Pvt. Ltd	-	A Heterozygous Splice site region variant c.2347-7A>G in Exon 16 of the SETD5 gene that results in the amino acid substitution was identified. The observed variant is novel in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic (ClinVar ID: 280376). Published functional studies demonstrate a damaging effect (insertion of a 6-bp intronic sequence causing a premature stop codon and nonsense-mediated mRNA decay). Patients clinical presentations included cognitive delay, growth retardation, autism spectrum disorder, attention deficit hyperactivity disorder, unsteady gait, heart defects, and craniofacial dysmorphism (Kobayashi Y et al., 2016, Powis Z et al., 2018). Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines. -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Dec 21, 2023	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with intellectual developmental disorder, autosomal dominant 23 (MIM#615761). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Some mildly affected parents with the same SETD5 variant as their more severely affected children have been reported (PMID: 28881385, 27375234). (I) 0210 - Splice site variant proven to affect splicing of the transcript with a known effect on protein sequence. Published functional studies using RT-PCR and next generation sequencing on a patient-derived lymphoblastoid cell line identified a 6bp insertion within the intronic sequence, introducing a premature stop codon and resulting in subsequent nonsense-mediated mRNA decay (PMID: 26482601). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic in at least 11 individuals with SETD5-related features, six of which were confirmed de novo (ClinVar, PMIDs: 26482601, 28881385). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	clinical testing	New York Genome Center	Jun 26, 2020	The de novo heterozygous c.2347-7A>G splice region variant identified in the SETD5 gene has been reported in at least 4 individuals affected with a neurological disorder [PMID: 26482601; PMID:28881385]. Patients' clinical presentations included cognitive delay, growth retardation, autism spectrum disorder, attention deficit hyperactivity disorder, unsteady gait, heart defects, and craniofacial dysmorphism [PMID: 26482601; PMID:28881385]. Analysis of cDNA obtained from a patient derived lymphoblastoid cell lineshowed that this splice region variant introduces premature stop codon and the mutant mRNA is subjected to nonsense mediated decay [PMID: 26482601]. This variant has been reported as Pathogenic in ClinVar database by two independent laboratories [Variation ID:280376]. This variant is absent from gnomAD suggesting it is an extremely rare allele in the populations represented in this database. Based on the available evidence, the de novo c.2347-7A>G splice region variant identified in the SETD5 gene is reported as Pathogenic. -

not provided Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 25, 2022	Published functional studies demonstrate a damaging effect (insertion of a 6-bp intronic sequence causing a premature stop codon and nonsense-mediated mRNA decay) (Kobayashi et al., 2016); Not observed in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 33490948, 26482601, 28881385) -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 04, 2016

- -

See cases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetics Laboratory, UDIAT-Centre Diagnòstic, Hospital Universitari Parc Tauli

Apr 26, 2021

PVS1_very strong;PS3_strong;PM2_supporting;PM6_moderate;BP4_supporting -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	22
DANN	Benign	0.59
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.97
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_AG_spliceai		1.0		Position offset: 1
DS_AL_spliceai		0.65		Position offset: 7

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs886041593; hg19: chr3-9495416;