rs75763513

Variant names:

• chr3-47103391-A-T
• rs75763513
• NM_014159.7:c.4872T>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_014159.7(SETD2):​c.4872T>A​(p.Ser1624Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00181 in 1,613,314 control chromosomes in the GnomAD database, including 50 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0099 (30 hom., cov: 32)
  • Exomes 𝑓: 0.00097 (20 hom.)
• Consequence: SETD2 NM_014159.7 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.786
• Publications: 1 publications found

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]

SETD2 Gene-Disease associations (from GenCC):

• Luscan-Lumish syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• SETD2-related neurodevelopmental disorder without or with macrocephaly/overgrowth

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• Rabin-Pappas syndrome

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• SETD2-related microcephaly-severe intellectual disability-multiple congenital anomalies syndrome

  Inheritance: AD Classification: STRONG Submitted by: ClinGen
• Sotos syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• intellectual developmental disorder, autosomal dominant 70

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 3-47103391-A-T is Benign according to our data. Variant chr3-47103391-A-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 475521.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00989 (1507/152308) while in subpopulation AFR AF = 0.035 (1453/41554). AF 95% confidence interval is 0.0335. There are 30 homozygotes in GnomAd4. There are 703 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1507 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014159.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SETD2	NM_014159.7	MANE Select	c.4872T>A	p.Ser1624Ser	synonymous	Exon 7 of 21	NP_054878.5
	SETD2	NM_001349370.3		c.4740T>A	p.Ser1580Ser	synonymous	Exon 6 of 20	NP_001336299.1	A0A1W2PPX9
	SETD2	NR_146158.3		n.5061T>A		non_coding_transcript_exon	Exon 7 of 22

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SETD2	ENST00000409792.4	TSL:5 MANE Select	c.4872T>A	p.Ser1624Ser	synonymous	Exon 7 of 21	ENSP00000386759.3	Q9BYW2-1
	SETD2	ENST00000330022.11	TSL:1	n.*595T>A		non_coding_transcript_exon	Exon 5 of 19	ENSP00000332415.7	H7BXT4
	SETD2	ENST00000330022.11	TSL:1	n.*595T>A		3_prime_UTR	Exon 5 of 19	ENSP00000332415.7	H7BXT4

Frequencies

GnomAD3 genomes AF: 0.00989 AC: 1505 AN: 152190 Hom.: 29 Cov.: 32

Gnomad AFR AF: 0.0350

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00223

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00718

GnomAD2 exomes AF: 0.00261 AC: 655 AN: 251366 AF XY: 0.00183

Gnomad AFR exome AF: 0.0378

Gnomad AMR exome AF: 0.000954

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000971 AC: 1418 AN: 1461006 Hom.: 20 Cov.: 28 AF XY: 0.000810 AC XY: 589 AN XY: 726838

African (AFR) AF: 0.0366 AC: 1225 AN: 33436

American (AMR) AF: 0.00152 AC: 68 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39646

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53388

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5764

European-Non Finnish (NFE) AF: 0.00000990 AC: 11 AN: 1111326

Other (OTH) AF: 0.00184 AC: 111 AN: 60364

GnomAD4 genome AF: 0.00989 AC: 1507 AN: 152308 Hom.: 30 Cov.: 32 AF XY: 0.00944 AC XY: 703 AN XY: 74484

African (AFR) AF: 0.0350 AC: 1453 AN: 41554

American (AMR) AF: 0.00222 AC: 34 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68024

Other (OTH) AF: 0.00710 AC: 15 AN: 2112

Alfa AF: 0.00290 Hom.: 0

Bravo AF: 0.0113

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.0000546

EpiControl AF: 0.000119

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Luscan-Lumish syndrome (2)
-	-	2	not provided (2)
-	-	1	not specified (1)
-	-	1	SETD2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	8.5
DANN	Benign	0.73
PhyloP100		0.79
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs75763513; hg19: chr3-47144881;