3-9448586-C-T

Variant names:

• chr3-9448586-C-T
• rs864321657
• NM_001080517.3:c.2302C>T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001080517.3(SETD5):​c.2302C>T​(p.Arg768*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SETD5 NM_001080517.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 3.01

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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-9448586-C-T is Pathogenic according to our data. Variant chr3-9448586-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 219198.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-9448586-C-T is described in Lovd as [Pathogenic]. Variant chr3-9448586-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SETD5	NM_001080517.3	c.2302C>T	p.Arg768*	stop_gained	Exon 16 of 23	ENST00000402198.7	NP_001073986.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SETD5	ENST00000402198.7	c.2302C>T	p.Arg768*	stop_gained	Exon 16 of 23	5	NM_001080517.3	ENSP00000385852.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency Pathogenic:5

Feb 14, 2020

Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting+PS2_Supporting+PVS1+PS4_Supporting -

Jan 27, 2022

Daryl Scott Lab, Baylor College of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 11, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.5, 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) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (v2, v3 and v4). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Many NMD-predicted variants have been reported as pathogenic and likely-pathogenic (ClinVar, DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic or likely pathogenic in multiple individuals, including five individuals in whom the variant was de novo (PMIDs: 25138099, 23020937, 28990276, ClinVar, DECIPHER). (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 -

Nov 10, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:2

Feb 15, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24859339, 25138099, 28263952, 28990276, 28191890, 23020937, 31785789, 32299058) -

Oct 29, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg768*) in the SETD5 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SETD5 are known to be pathogenic (PMID: 24680889). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of SETD5-related neurodevelopmental disorder (PMID: 25138099, 28990276). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 219198). For these reasons, this variant has been classified as Pathogenic. -

Inborn genetic diseases Pathogenic:1

Sep 13, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2302C>T (p.R768*) alteration, located in exon 16 (coding exon 14) of the SETD5 gene, consists of a C to T substitution at nucleotide position 2302. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 768. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been reported in multiple individuals with features consistent with SETD5-related neurodevelopmental disorder, and occurred de novo in at least one individual (Kuechler, 2015; Zhao, 2017). Based on the available evidence, this alteration is classified as pathogenic. -

Neurodevelopmental disorder Pathogenic:1

Apr 02, 2020

Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.98	D
Vest4		0.48
ClinPred		1.0	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs864321657; hg19: chr3-9490270; COSMIC: COSV56718620; COSMIC: COSV56718620;