3-47088119-G-A

Variant names:

• chr3-47088119-G-A
• rs144825663
• NM_014159.7:c.5271C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_014159.7(SETD2):​c.5271C>T​(p.Leu1757Leu) 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
• 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: 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

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 475524.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 578 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SETD2	NM_014159.7	MANE Select	c.5271C>T	p.Leu1757Leu	synonymous	Exon 10 of 21	NP_054878.5
	SETD2	NM_001349370.3		c.5139C>T	p.Leu1713Leu	synonymous	Exon 9 of 20	NP_001336299.1
	SETD2	NR_146158.3		n.5460C>T		non_coding_transcript_exon	Exon 10 of 22

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SETD2	ENST00000409792.4	TSL:5 MANE Select	c.5271C>T	p.Leu1757Leu	synonymous	Exon 10 of 21	ENSP00000386759.3
	SETD2	ENST00000330022.11	TSL:1	n.*994C>T		non_coding_transcript_exon	Exon 8 of 19	ENSP00000332415.7
	SETD2	ENST00000330022.11	TSL:1	n.*994C>T		3_prime_UTR	Exon 8 of 19	ENSP00000332415.7

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

GnomAD2 exomes AF: 0.00327 AC: 814 AN: 249006 AF XY: 0.00314

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 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

African (AFR) AF: 0.000929 AC: 31 AN: 33366

American (AMR) AF: 0.00120 AC: 53 AN: 44180

Ashkenazi Jewish (ASJ) AF: 0.00491 AC: 128 AN: 26090

East Asian (EAS) AF: 0.00 AC: 0 AN: 39672

South Asian (SAS) AF: 0.00109 AC: 93 AN: 85658

European-Finnish (FIN) AF: 0.00441 AC: 234 AN: 53102

Middle Eastern (MID) AF: 0.000521 AC: 3 AN: 5762

European-Non Finnish (NFE) AF: 0.00649 AC: 7209 AN: 1111342

Other (OTH) AF: 0.00540 AC: 326 AN: 60322

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

African (AFR) AF: 0.00116 AC: 48 AN: 41546

American (AMR) AF: 0.00131 AC: 20 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00461 AC: 16 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4824

European-Finnish (FIN) AF: 0.00378 AC: 40 AN: 10594

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00653 AC: 444 AN: 68026

Other (OTH) AF: 0.00189 AC: 4 AN: 2112

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

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Sep 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SETD2: BP4, BP7, BS2

Mar 30, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Luscan-Lumish syndrome Benign:2

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 15, 2022

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	3.3
DANN	Benign	0.68
PhyloP100		0.32
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs144825663; hg19: chr3-47129609;