rs780263494

Variant names:

• chr3-9434876-A-G
• rs780263494
• NM_001080517.3:c.382A>G
• SETD5 p.Ile128Val

Your query was ambiguous. Multiple possible variants found:

• chr3-9434876-A-G
• chr3-9434876-A-C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001080517.3(SETD5):​c.382A>G​(p.Ile128Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000105 in 1,613,312 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: SETD5 NM_001080517.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.025382757).
• BP6: Variant 3-9434876-A-G is Benign according to our data. Variant chr3-9434876-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 235575.
• BS2: High AC in GnomAdExome4 at 14 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SETD5	NM_001080517.3	MANE Select	c.382A>G	p.Ile128Val	missense	Exon 6 of 23	NP_001073986.1	Q9C0A6-1
	SETD5	NM_001437635.1		c.439A>G	p.Ile147Val	missense	Exon 6 of 24	NP_001424564.1
	SETD5	NM_001437633.1		c.439A>G	p.Ile147Val	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>G	p.Ile128Val	missense	Exon 6 of 23	ENSP00000385852.2	Q9C0A6-1
	SETD5	ENST00000493918.5	TSL:1	n.546A>G		non_coding_transcript_exon	Exon 2 of 19
	SETD5	ENST00000682536.1		c.439A>G	p.Ile147Val	missense	Exon 6 of 24	ENSP00000507956.1	A0A804HKJ9

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152200 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000202 AC: 5 AN: 248024 AF XY: 0.0000223

Gnomad AFR exome AF: 0.0000651

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000178

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1461112 Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 10 AN XY: 726764

African (AFR) AF: 0.0000598 AC: 2 AN: 33452

American (AMR) AF: 0.00 AC: 0 AN: 44630

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.0000930 AC: 8 AN: 86054

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53380

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111664

Other (OTH) AF: 0.0000166 AC: 1 AN: 60360

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152200 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74366

African (AFR) AF: 0.0000241 AC: 1 AN: 41446

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000386 Hom.: 0

Bravo AF: 0.0000264

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	22
DANN	Benign	0.53
DEOGEN2	Benign	0.0056	T
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.025	T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	-1.8	N
PhyloP100		4.7
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	0.080	N
REVEL	Benign	0.24
Sift	Benign	0.73	T
Sift4G	Benign	1.0	T
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.7
Varity_R		0.023
gMVP		0.21
Mutation Taster		=99/1	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

dbSNP: rs780263494;

hg19: chr3-9476560;