3-9433889-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001080517.3(SETD5):c.116T>G(p.Val39Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SETD5 NM_001080517.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.18

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.42283756).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SETD5	NM_001080517.3	c.116T>G	p.Val39Gly	missense_variant	4/23	ENST00000402198.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SETD5	ENST00000402198.7	c.116T>G	p.Val39Gly	missense_variant	4/23	5	NM_001080517.3	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

SETD5-related syndromic intellectual disability Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Dec 16, 2020

The SETD5 c.116T>G (p.Val39Gly) variant is a missense variant. A literature search was performed for the gene, cDNA change, and amino acid change. No publications were found based on this search. This variant is not found in the Genome Aggregation Database in a region of good sequence coverage, so the variant is presumed to be rare. Based on the limited evidence, the p.Val39Gly variant is classified as a variant of uncertain significance for SETD5-related syndromic intellectual disability. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
Cadd	Pathogenic	26
Dann	Uncertain	0.98
DEOGEN2	Benign	0.027	T;T;T;T
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.71	T;T;.;T
M_CAP	Uncertain	0.087	D
MetaRNN	Benign	0.42	T;T;T;T
MetaSVM	Uncertain	0.34	D
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-0.46	N;N;N;N
REVEL	Uncertain	0.44
Sift	Benign	0.085	T;T;T;T
Sift4G	Benign	0.089	T;T;T;T
Polyphen		0.70	.;P;P;.
Vest4		0.65, 0.63, 0.61
MutPred		0.28		Loss of stability (P = 0.0038);Loss of stability (P = 0.0038);Loss of stability (P = 0.0038);Loss of stability (P = 0.0038);
MVP		0.80
MPC		1.6
ClinPred		0.53	D
GERP RS		6.1
Varity_R		0.17
gMVP		0.42

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

LitVar

Other links and lift over

dbSNP: rs1575376916; hg19: chr3-9475573;