rs369333306

chr3-47124161-T-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_014159.7(SETD2):c.475A>G(p.Thr159Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000238 in 1,551,818 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: SETD2 NM_014159.7 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.53

Genes affected

SETD2 (HGNC:18420): (SET domain containing 2, histone lysine methyltransferase) Huntington's disease (HD), a neurodegenerative disorder characterized by loss of striatal neurons, is caused by an expansion of a polyglutamine tract in the HD protein huntingtin. This gene encodes a protein belonging to a class of huntingtin interacting proteins characterized by WW motifs. This protein is a histone methyltransferase that is specific for lysine-36 of histone H3, and methylation of this residue is associated with active chromatin. This protein also contains a novel transcriptional activation domain and has been found associated with hyperphosphorylated RNA polymerase II. [provided by RefSeq, Aug 2008]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, SETD2
• BP4: Computational evidence support a benign effect (MetaRNN=0.03259319).
• BP6: Variant 3-47124161-T-C is Benign according to our data. Variant chr3-47124161-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 475520.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0000328 (5/152240) while in subpopulation SAS AF= 0.000207 (1/4832). AF 95% confidence interval is 0.0000325. There are 0 homozygotes in gnomad4. There are 3 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SETD2	NM_014159.7	c.475A>G	p.Thr159Ala	missense_variant	3/21	ENST00000409792.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SETD2	ENST00000409792.4	c.475A>G	p.Thr159Ala	missense_variant	3/21	5	NM_014159.7	P3

Frequencies

GnomAD3 genomes AF: 0.0000328 AC: 5 AN: 152240 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000254 AC: 4 AN: 157618 Hom.: 0 AF XY: 0.0000240 AC XY: 2 AN XY: 83298

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000878

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000163

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000229 AC: 32 AN: 1399578 Hom.: 0 Cov.: 33 AF XY: 0.0000261 AC XY: 18 AN XY: 690296

Gnomad4 AFR exome AF: 0.0000949

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000114

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000649

Gnomad4 OTH exome AF: 0.000155

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152240 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74378

Gnomad4 AFR AF: 0.0000965

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000847 Hom.: 0

Bravo AF: 0.0000340

ESP6500AA AF: 0.000723 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000380 AC: 1

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Luscan-Lumish syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Mar 19, 2022

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jun 01, 2022

SETD2: BP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.29
Cadd	Benign	2.9
Dann	Benign	0.30
DEOGEN2	Benign	0.053	T;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.045	N
LIST_S2	Benign	0.48	T;T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.033	T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	0.0	N;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.12	N;N
REVEL	Benign	0.085
Sift	Benign	0.85	T;T
Sift4G	Benign	0.52	T;.
Polyphen		0.0	B;.
Vest4		0.12
MVP		0.76
MPC		0.25
ClinPred		0.0047	T
GERP RS		-2.5
Varity_R		0.019
gMVP		0.16

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: rs369333306; hg19: chr3-47165651; COSMIC: COSV105212516; COSMIC: COSV105212516;