rs886041593

Variant names:

• chr3-9453732-A-G
• rs886041593
• NM_001080517.3:c.2347-7A>G

Your query was ambiguous. Multiple possible variants found:

• chr3-9453732-A-G
• chr3-9453732-A-T

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PS3 PM2 PP3 PP5_Very_Strong

The NM_001080517.3(SETD5):​c.2347-7A>G variant causes a splice region, 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 (★★). ClinVar reports functional evidence for this variant: "SCV000330285: 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)" and additional evidence is available in ClinVar.

• Frequency: Genomes: not found (cov: 31)
• Consequence: SETD5 NM_001080517.3 splice_region, intron
• Scores: Splicing: ADA: 0.9995
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: -0.397
• Publications: 0 publications found

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]

SETD5 Gene-Disease associations (from GenCC):

• intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P, Orphanet
• syndromic complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 15 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000330285: 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); SCV000741431: One functional study demonstrated that this alteration results in abnormal splicing (Kobayashi, 2016).; SCV001761129: Analysis of cDNA obtained from a patient derived lymphoblastoid cell line showed that this splice region variant introduces premature stop codon and the mutant mRNA is subjected to nonsense mediated decay [PMID: 26482601].; SCV003915915: 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 Y et al., 2016, Powis Z et al., 2018).; SCV005086051: 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).
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious 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 VariationId is 280376.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001080517.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SETD5	NM_001080517.3	MANE Select	c.2347-7A>G		splice_region intron	N/A	NP_001073986.1	Q9C0A6-1
	SETD5	NM_001437635.1		c.2404-7A>G		splice_region intron	N/A	NP_001424564.1
	SETD5	NM_001437633.1		c.2443-7A>G		splice_region intron	N/A	NP_001424562.1	A0A804HKJ9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SETD5	ENST00000402198.7	TSL:5 MANE Select	c.2347-7A>G		splice_region intron	N/A	ENSP00000385852.2	Q9C0A6-1
	SETD5	ENST00000493918.5	TSL:1	n.2511-7A>G		splice_region intron	N/A
	SETD5	ENST00000682536.1		c.2443-7A>G		splice_region intron	N/A	ENSP00000507956.1	A0A804HKJ9

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency (3)
3	-	-	not provided (3)
1	-	-	Inborn genetic diseases (1)
1	-	-	Intellectual disability (1)
1	-	-	See cases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	22
DANN	Benign	0.59
PhyloP100		-0.40
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=8/92	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs886041593; hg19: chr3-9495416;