rs75248784

Variant names:

• chr3-47122093-G-A
• rs75248784
• NM_014159.7:c.2543C>T

Your query was ambiguous. Multiple possible variants found:

• chr3-47122093-G-A
• chr3-47122093-G-C
• chr3-47122093-G-T

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.2543C>T​(p.Ala848Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00151 in 1,613,772 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0080 (16 hom., cov: 32)
  • Exomes 𝑓: 0.00083 (22 hom.)
• Consequence: SETD2 NM_014159.7 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7 O:1
• Conservation: PhyloP100: 2.14
• Publications: 4 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: G2P, Labcorp Genetics (formerly Invitae), 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: Labcorp Genetics (formerly Invitae), G2P, 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

ENSG00000296084 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0052988827).
• BP6: Variant 3-47122093-G-A is Benign according to our data. Variant chr3-47122093-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 135221.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 = 0.00798 (1215/152244) while in subpopulation AFR AF = 0.0285 (1182/41540). AF 95% confidence interval is 0.0271. There are 16 homozygotes in GnomAd4. There are 567 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1215 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.2543C>T	p.Ala848Val	missense	Exon 3 of 21	NP_054878.5
	SETD2	NM_001349370.3		c.2411C>T	p.Ala804Val	missense	Exon 2 of 20	NP_001336299.1
	SETD2	NR_146158.3		n.2732C>T		non_coding_transcript_exon	Exon 3 of 22

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SETD2	ENST00000409792.4	TSL:5 MANE Select	c.2543C>T	p.Ala848Val	missense	Exon 3 of 21	ENSP00000386759.3
	SETD2	ENST00000330022.11	TSL:1	n.2156C>T		non_coding_transcript_exon	Exon 1 of 19	ENSP00000332415.7
	SETD2	ENST00000952253.1		c.2543C>T	p.Ala848Val	missense	Exon 3 of 20	ENSP00000622312.1

Frequencies

GnomAD3 genomes AF: 0.00799 AC: 1216 AN: 152126 Hom.: 16 Cov.: 32

Gnomad AFR AF: 0.0286

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

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: 0.0000147

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00192 AC: 480 AN: 250458 AF XY: 0.00134

Gnomad AFR exome AF: 0.0278

Gnomad AMR exome AF: 0.000724

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000265

Gnomad OTH exome AF: 0.000493

GnomAD4 exome AF: 0.000831 AC: 1215 AN: 1461528 Hom.: 22 Cov.: 34 AF XY: 0.000686 AC XY: 499 AN XY: 727064

African (AFR) AF: 0.0324 AC: 1083 AN: 33464

American (AMR) AF: 0.000872 AC: 39 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53198

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.00000899 AC: 10 AN: 1111936

Other (OTH) AF: 0.00132 AC: 80 AN: 60390

GnomAD4 genome AF: 0.00798 AC: 1215 AN: 152244 Hom.: 16 Cov.: 32 AF XY: 0.00762 AC XY: 567 AN XY: 74448

African (AFR) AF: 0.0285 AC: 1182 AN: 41540

American (AMR) AF: 0.00164 AC: 25 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68016

Other (OTH) AF: 0.00331 AC: 7 AN: 2112

Alfa AF: 0.00292 Hom.: 13

Bravo AF: 0.00921

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0263 AC: 116

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00237 AC: 288

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Luscan-Lumish syndrome (2)
-	-	2	not specified (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.099	T
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.72	T
MetaRNN	Benign	0.0053	T
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	0.69	N
PhyloP100		2.1
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.87	N
REVEL	Benign	0.16
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.031	D
Polyphen		0.0010	B
Vest4		0.079
MVP		0.62
MPC		0.26
ClinPred		0.010	T
GERP RS		2.5
PromoterAI		-0.0058	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.061
gMVP		0.21
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs75248784; hg19: chr3-47163583;