3-9439909-A-G

Variant names:

• chr3-9439909-A-G
• rs17050346
• NM_001080517.3:c.568-547A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001080517.3(SETD5):​c.568-547A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0599 in 151,828 control chromosomes in the GnomAD database, including 404 homozygotes. 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: 𝑓 0.060 (404 hom., cov: 32)
• Consequence: SETD5 NM_001080517.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.18
• 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.113 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SETD5	NM_001080517.3	c.568-547A>G		intron_variant	Intron 7 of 22	ENST00000402198.7	NP_001073986.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SETD5	ENST00000402198.7	c.568-547A>G		intron_variant	Intron 7 of 22	5	NM_001080517.3	ENSP00000385852.2

Frequencies

GnomAD3 genomes AF: 0.0598 AC: 9066 AN: 151712 Hom.: 399 Cov.: 32

Gnomad AFR AF: 0.0928

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.117

Gnomad ASJ AF: 0.0144

Gnomad EAS AF: 0.0907

Gnomad SAS AF: 0.0557

Gnomad FIN AF: 0.0375

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0319

Gnomad OTH AF: 0.0551

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0599 AC: 9102 AN: 151828 Hom.: 404 Cov.: 32 AF XY: 0.0613 AC XY: 4553 AN XY: 74274

African (AFR) AF: 0.0931 AC: 3830 AN: 41130

American (AMR) AF: 0.117 AC: 1793 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.0144 AC: 50 AN: 3470

East Asian (EAS) AF: 0.0907 AC: 470 AN: 5180

South Asian (SAS) AF: 0.0557 AC: 269 AN: 4828

European-Finnish (FIN) AF: 0.0375 AC: 398 AN: 10616

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0319 AC: 2169 AN: 68012

Other (OTH) AF: 0.0546 AC: 115 AN: 2108

Alfa AF: 0.0423 Hom.: 71

Bravo AF: 0.0676

Asia WGS AF: 0.0600 AC: 206 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	5.0
DANN	Benign	0.54
PhyloP100		1.2
Mutation Taster		=100/0	polymorphism (auto)

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

dbSNP: rs17050346; hg19: chr3-9481593;