3-9428951-A-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001080517.3(SETD5):c.13A>G(p.Ile5Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000198 in 1,613,136 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I5N) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: SETD5 NM_001080517.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 3.27

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 Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.065442145).
• BP6: Variant 3-9428951-A-G is Benign according to our data. Variant chr3-9428951-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1367201.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.
• BS2: High AC in GnomAdExome at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SETD5	NM_001080517.3	c.13A>G	p.Ile5Val	missense_variant	3/23	ENST00000402198.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SETD5	ENST00000402198.7	c.13A>G	p.Ile5Val	missense_variant	3/23	5	NM_001080517.3	P4

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152144 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000242 AC: 6 AN: 248338 Hom.: 0 AF XY: 0.0000223 AC XY: 3 AN XY: 134664

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000111

Gnomad SAS exome AF: 0.0000658

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000888

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000192 AC: 28 AN: 1460874 Hom.: 0 Cov.: 29 AF XY: 0.0000206 AC XY: 15 AN XY: 726720

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.0000448

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.0000117

Gnomad4 OTH exome AF: 0.0000332

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152262 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74462

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000416

ExAC AF: 0.0000248 AC: 3

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Aug 09, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 27, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.30
Cadd	Benign	18
Dann	Benign	0.94
DEOGEN2	Benign	0.026	T;T;T;T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.26
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.86	D;D;.;D
M_CAP	Benign	0.050	D
MetaRNN	Benign	0.065	T;T;T;T
MetaSVM	Benign	-0.40	T
MutationTaster	Benign	1.0	D;N;N;N
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.68	N;N;N;N
REVEL	Benign	0.24
Sift	Benign	0.10	T;T;T;T
Sift4G	Benign	0.18	T;T;T;T
Polyphen		0.0010	.;B;B;.
Vest4		0.14, 0.16, 0.23
MutPred		0.23		Loss of sheet (P = 0.1398);Loss of sheet (P = 0.1398);Loss of sheet (P = 0.1398);Loss of sheet (P = 0.1398);
MVP		0.10
MPC		0.43
ClinPred		0.031	T
GERP RS		-1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.032
gMVP		0.39

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: rs567415895; hg19: chr3-9470635;