Genetic Variant SETD5:p.Arg768Arg (chr3-9448586-C-A) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2BP4_ModerateBP7BS2

The NM_001080517.3(SETD5):c.2302C>A(p.Arg768Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000343 in 1,457,026 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

SETD5
NM_001080517.3 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.01

Publications

8 publications found

Variant links:

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

SETD5 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.34).

BP7

Synonymous conserved (PhyloP=3.01 with no splicing effect.

BS2

High AC in GnomAdExome4 at 5 AD gene.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SETD5	NM_001080517.3	MANE Select	c.2302C>A	p.Arg768Arg	synonymous	Exon 16 of 23	NP_001073986.1
SETD5	NM_001437635.1		c.2359C>A	p.Arg787Arg	synonymous	Exon 16 of 24	NP_001424564.1
SETD5	NM_001437633.1		c.2398C>A	p.Arg800Arg	synonymous	Exon 17 of 24	NP_001424562.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SETD5	ENST00000402198.7	TSL:5 MANE Select	c.2302C>A	p.Arg768Arg	synonymous	Exon 16 of 23	ENSP00000385852.2
SETD5	ENST00000493918.5	TSL:1	n.2466C>A		non_coding_transcript_exon	Exon 12 of 19
SETD5	ENST00000682536.1		c.2398C>A	p.Arg800Arg	synonymous	Exon 17 of 24	ENSP00000507956.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000343

AC:

AN:

1457026

Hom.:

Cov.:

AF XY:

0.00000552

AC XY:

AN XY:

724176

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33410

American (AMR)

AF:

0.00

AC:

AN:

44474

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25894

East Asian (EAS)

AF:

0.00

AC:

AN:

39588

South Asian (SAS)

AF:

0.00

AC:

AN:

85778

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53312

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5742

European-Non Finnish (NFE)

AF:

0.00000451

AC:

AN:

1108624

Other (OTH)

AF:

0.00

AC:

AN:

60204

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.545

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.34

CADD

Benign

(source)

DANN

Benign

0.60

PhyloP100

3.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over