3-9428946-T-C

Variant names:

• chr3-9428946-T-C
• NM_001080517.3:c.8T>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001292043.2(SETD5):​c.-551T>C variant causes a 5 prime UTR premature start codon gain change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SETD5 NM_001292043.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.39
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001292043.2. 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.8T>C	p.Ile3Thr	missense	Exon 3 of 23	NP_001073986.1	Q9C0A6-1
	SETD5	NM_001292043.2		c.-551T>C		5_prime_UTR_premature_start_codon_gain	Exon 3 of 25	NP_001278972.1	Q9C0A6-3
	SETD5	NM_001349451.2		c.-592T>C		5_prime_UTR_premature_start_codon_gain	Exon 3 of 26	NP_001336380.1	Q9C0A6-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SETD5	ENST00000402198.7	TSL:5 MANE Select	c.8T>C	p.Ile3Thr	missense	Exon 3 of 23	ENSP00000385852.2	Q9C0A6-1
	SETD5	ENST00000683012.1		c.-144T>C		5_prime_UTR_premature_start_codon_gain	Exon 2 of 4	ENSP00000506933.1	A0A804HI72
	SETD5	ENST00000682536.1		c.8T>C	p.Ile3Thr	missense	Exon 3 of 24	ENSP00000507956.1	A0A804HKJ9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.32	D
MetaRNN	Uncertain	0.74	D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		7.4
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-4.4	D
REVEL	Pathogenic	0.66
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.92
MutPred		0.32		Loss of sheet (P = 0.007)
MVP		0.77
MPC		1.6
ClinPred		0.98	D
GERP RS		6.2
PromoterAI		-0.010	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.39
gMVP		0.65
Mutation Taster		=46/54	disease causing

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

Other links and lift over

hg19: chr3-9470630;