rs1553623867

Variant names:

• chr3-9445647-T-C
• rs1553623867
• NM_001080517.3:c.1441-10T>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001080517.3(SETD5):​c.1441-10T>C variant causes a 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SETD5 NM_001080517.3 intron
• Scores: Splicing: ADA: 0.4751
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.62
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).

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.1441-10T>C		intron	N/A	NP_001073986.1	Q9C0A6-1
	SETD5	NM_001437635.1		c.1498-10T>C		intron	N/A	NP_001424564.1
	SETD5	NM_001437633.1		c.1537-10T>C		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.1441-10T>C		intron	N/A	ENSP00000385852.2	Q9C0A6-1
	SETD5	ENST00000493918.5	TSL:1	n.1605-10T>C		intron	N/A
	SETD5	ENST00000682536.1		c.1537-10T>C		intron	N/A	ENSP00000507956.1	A0A804HKJ9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Pathogenic	33
DANN	Uncertain	0.99
PhyloP100		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.48
dbscSNV1_RF	Benign	0.49
SpliceAI score (max)		0.60		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.60		Position offset: -27
DS_AL_spliceai		0.25		Position offset: 10

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

Other links and lift over

dbSNP: rs1553623867; hg19: chr3-9487331;