3-9428952-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP6_Moderate

The NM_001080517.3(SETD5):c.14T>A(p.Ile5Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,876 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I5V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SETD5 NM_001080517.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 7.39

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 3-9428952-T-A is Benign according to our data. Variant chr3-9428952-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 2181850.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SETD5	NM_001080517.3	c.14T>A	p.Ile5Asn	missense_variant	3/23	ENST00000402198.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SETD5	ENST00000402198.7	c.14T>A	p.Ile5Asn	missense_variant	3/23	5	NM_001080517.3	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000403 AC: 1 AN: 248336 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134666

Gnomad AFR exome AF: 0.0000649

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460876 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 726698

Gnomad4 AFR exome AF: 0.0000897

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000843 Hom.: 0

Bravo AF: 0.0000151

ESP6500AA AF: 0.000249 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00000827 AC: 1

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Sep 14, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Uncertain	0.082	D
BayesDel_noAF	Uncertain	0.060
Cadd	Uncertain	26
Dann	Uncertain	0.99
DEOGEN2	Benign	0.14	T;T;T;T
Eigen	Uncertain	0.65
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.97	D;D;.;D
M_CAP	Pathogenic	0.33	D
MetaRNN	Uncertain	0.71	D;D;D;D
MetaSVM	Pathogenic	0.80	D
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-5.9	D;D;D;D
REVEL	Uncertain	0.56
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		0.95	.;P;P;.
Vest4		0.67, 0.91, 0.73
MVP		0.18
MPC		1.8
ClinPred		0.96	D
GERP RS		6.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.72
gMVP		0.77

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: rs377000906; hg19: chr3-9470636;