SETD5 p.Ile128Leu

Variant names:

• chr3-9434876-A-T
• NM_001080517.3:c.382A>T
• SETD5 p.Ile128Leu

Your query was ambiguous. Multiple possible variants found:

• chr3-9434876-A-T
• chr3-9434876-A-C
• chr3-9434876-ATA-TTG
• chr3-9434876-ATA-CTT
• chr3-9434876-ATA-CTC
• chr3-9434876-ATA-CTG

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001080517.3(SETD5):​c.382A>T​(p.Ile128Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I128V) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SETD5 NM_001080517.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.72
• 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: G2P, Orphanet, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• syndromic complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09526473).

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.382A>T	p.Ile128Leu	missense	Exon 6 of 23	NP_001073986.1	Q9C0A6-1
	SETD5	NM_001437635.1		c.439A>T	p.Ile147Leu	missense	Exon 6 of 24	NP_001424564.1
	SETD5	NM_001437633.1		c.439A>T	p.Ile147Leu	missense	Exon 6 of 24	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.382A>T	p.Ile128Leu	missense	Exon 6 of 23	ENSP00000385852.2	Q9C0A6-1
	SETD5	ENST00000493918.5	TSL:1	n.546A>T		non_coding_transcript_exon	Exon 2 of 19
	SETD5	ENST00000682536.1		c.439A>T	p.Ile147Leu	missense	Exon 6 of 24	ENSP00000507956.1	A0A804HKJ9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Uncertain	0.050	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	23
DANN	Benign	0.92
DEOGEN2	Benign	0.0058	T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.11
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.095	T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	-0.55	N
PhyloP100		4.7
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-0.010	N
REVEL	Benign	0.22
Sift	Benign	0.28	T
Sift4G	Benign	0.53	T
Varity_R		0.047
gMVP		0.25
Mutation Taster		=97/3	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr3-9476560;