rs587777325

Variant names:

• chr3-9445055-A-G
• rs587777325
• NM_001080517.3:c.1195A>G

Your query was ambiguous. Multiple possible variants found:

• chr3-9445055-A-G
• chr3-9445055-A-T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001437635.1(SETD5):​c.1252A>G​(p.Lys418Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SETD5 NM_001437635.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.82
• Publications: 2 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: Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• syndromic complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.786

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001437635.1. 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.1195A>G	p.Lys399Glu	missense	Exon 12 of 23	NP_001073986.1
	SETD5	NM_001437635.1		c.1252A>G	p.Lys418Glu	missense	Exon 12 of 24	NP_001424564.1
	SETD5	NM_001437633.1		c.1291A>G	p.Lys431Glu	missense	Exon 13 of 24	NP_001424562.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SETD5	ENST00000402198.7	TSL:5 MANE Select	c.1195A>G	p.Lys399Glu	missense	Exon 12 of 23	ENSP00000385852.2
	SETD5	ENST00000493918.5	TSL:1	n.1359A>G		non_coding_transcript_exon	Exon 8 of 19
	SETD5	ENST00000682536.1		c.1291A>G	p.Lys431Glu	missense	Exon 13 of 24	ENSP00000507956.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.79	D
MetaSVM	Uncertain	0.32	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		8.8
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-2.5	N
REVEL	Pathogenic	0.73
Sift	Uncertain	0.021	D
Sift4G	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.89
MutPred		0.45		Loss of methylation at K418 (P = 0.0025)
MVP		0.70
MPC		1.7
ClinPred		0.96	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.55
gMVP		0.89
Mutation Taster		=36/64	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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

dbSNP: rs587777325; hg19: chr3-9486739;