3-9428963-G-T

Position:

• chr3-9428963-G-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_001080517.3(SETD5):​c.25G>T​(p.Val9Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000753 in 1,461,078 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: SETD5 NM_001080517.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.23

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SETD5	NM_001080517.3	c.25G>T	p.Val9Phe	missense_variant	3/23	ENST00000402198.7	NP_001073986.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SETD5	ENST00000402198.7	c.25G>T	p.Val9Phe	missense_variant	3/23	5	NM_001080517.3	ENSP00000385852.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000753 AC: 11 AN: 1461078 Hom.: 0 Cov.: 29 AF XY: 0.00000550 AC XY: 4 AN XY: 726792

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000900

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

May 21, 2020

A heterozygous missense variant was identified, NM_001080517.2(SETD5):c.25G>T in exon 3 of 23 of the SETD5 gene. (NB: this variant is non-coding in alternative transcripts). This substitution is predicted to create a minor amino acid change from a valine to a phenylalanine at position 9 of the protein; NP_001073986.1(SETD5):p.(Val9Phe). The valine at this position has high conservation (100 vertebrates, UCSC), but is not situated in a known functional domain (NCBI, PDB). In silico software predicts this variant to be damaging (PolyPhen2, SIFT, CADD, Mutation Taster). The variant is not present in the gnomAD population database and this variant has not previously been reported in clinical cases. Based on information available at the time of curation, this variant has been classified as a VUS. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T;T;T;T
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;.;D
M_CAP	Uncertain	0.28	D
MetaRNN	Uncertain	0.62	D;D;D;D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Uncertain	2.3	.;M;M;.
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-4.0	D;N;N;D
REVEL	Uncertain	0.55
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		0.86	.;P;P;.
Vest4		0.69, 0.84, 0.74
MutPred		0.24		Loss of glycosylation at T11 (P = 0.0907);Loss of glycosylation at T11 (P = 0.0907);Loss of glycosylation at T11 (P = 0.0907);Loss of glycosylation at T11 (P = 0.0907);
MVP		0.38
MPC		1.4
ClinPred		0.98	D
GERP RS		6.2
Varity_R		0.45
gMVP		0.74

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-9470647;