rs144825663

Positions:

• chr3-47088119-G-A
• chr3-47088119-G-C
• chr3-47088119-G-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_014159.7(SETD2):​c.5271C>T​(p.Leu1757=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00537 in 1,611,750 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0038 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0055 (33 hom.)
• Consequence: SETD2 NM_014159.7 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.323

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.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 3-47088119-G-A is Benign according to our data. Variant chr3-47088119-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 475524.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-47088119-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.323 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0038 (578/152256) while in subpopulation NFE AF= 0.00653 (444/68026). AF 95% confidence interval is 0.00603. There are 7 homozygotes in gnomad4. There are 262 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 578 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SETD2	NM_014159.7	c.5271C>T	p.Leu1757=	synonymous_variant	10/21	ENST00000409792.4	NP_054878.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SETD2	ENST00000409792.4	c.5271C>T	p.Leu1757=	synonymous_variant	10/21	5	NM_014159.7	ENSP00000386759	P3

Frequencies

GnomAD3 genomes AF: 0.00380 AC: 578 AN: 152138 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00116

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00378

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00653

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00327 AC: 814 AN: 249006 Hom.: 3 AF XY: 0.00314 AC XY: 422 AN XY: 134578

Gnomad AFR exome AF: 0.000802

Gnomad AMR exome AF: 0.00109

Gnomad ASJ exome AF: 0.00399

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00100

Gnomad FIN exome AF: 0.00359

Gnomad NFE exome AF: 0.00525

Gnomad OTH exome AF: 0.00395

GnomAD4 exome AF: 0.00553 AC: 8077 AN: 1459494 Hom.: 33 Cov.: 31 AF XY: 0.00536 AC XY: 3889 AN XY: 726012

Gnomad4 AFR exome AF: 0.000929

Gnomad4 AMR exome AF: 0.00120

Gnomad4 ASJ exome AF: 0.00491

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00109

Gnomad4 FIN exome AF: 0.00441

Gnomad4 NFE exome AF: 0.00649

Gnomad4 OTH exome AF: 0.00540

GnomAD4 genome AF: 0.00380 AC: 578 AN: 152256 Hom.: 7 Cov.: 32 AF XY: 0.00352 AC XY: 262 AN XY: 74444

Gnomad4 AFR AF: 0.00116

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.00461

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00378

Gnomad4 NFE AF: 0.00653

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00528 Hom.: 0

Bravo AF: 0.00337

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00339

EpiControl AF: 0.00397

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	SETD2: BP4, BP7, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 30, 2020	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Luscan-Lumish syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 19, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Mar 15, 2022	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	3.3
DANN	Benign	0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs144825663; hg19: chr3-47129609;