rs74485823

Variant names:

• chr3-47120316-T-A
• rs74485823
• NM_014159.7:c.4320A>T

Your query was ambiguous. Multiple possible variants found:

• chr3-47120316-T-A
• chr3-47120316-T-G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_014159.7(SETD2):​c.4320A>T​(p.Pro1440Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00148 in 1,613,926 control chromosomes in the GnomAD database, including 36 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P1440P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0078 (15 hom., cov: 32)
  • Exomes 𝑓: 0.00082 (21 hom.)
• Consequence: SETD2 NM_014159.7 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.00800
• 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, STRONG Submitted by: PanelApp Australia, ClinGen
• Rabin-Pappas syndrome

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

  Inheritance: AD Classification: STRONG Submitted by: ClinGen, PanelApp Australia
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 3-47120316-T-A is Benign according to our data. Variant chr3-47120316-T-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 475517.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.008 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0078 (1187/152266) while in subpopulation AFR AF = 0.0278 (1155/41558). AF 95% confidence interval is 0.0265. There are 15 homozygotes in GnomAd4. There are 554 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1187 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.4320A>T	p.Pro1440Pro	synonymous	Exon 3 of 21	NP_054878.5
	SETD2	NM_001349370.3		c.4188A>T	p.Pro1396Pro	synonymous	Exon 2 of 20	NP_001336299.1	A0A1W2PPX9
	SETD2	NR_146158.3		n.4509A>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.4320A>T	p.Pro1440Pro	synonymous	Exon 3 of 21	ENSP00000386759.3	Q9BYW2-1
	SETD2	ENST00000330022.11	TSL:1	n.3933A>T		non_coding_transcript_exon	Exon 1 of 19	ENSP00000332415.7	H7BXT4
	SETD2	ENST00000952253.1		c.4320A>T	p.Pro1440Pro	synonymous	Exon 3 of 20	ENSP00000622312.1

Frequencies

GnomAD3 genomes AF: 0.00780 AC: 1187 AN: 152148 Hom.: 15 Cov.: 32

Gnomad AFR AF: 0.0279

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: 0.00287

GnomAD2 exomes AF: 0.00191 AC: 478 AN: 250804 AF XY: 0.00132

Gnomad AFR exome AF: 0.0275

Gnomad AMR exome AF: 0.000697

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: 0.000491

GnomAD4 exome AF: 0.000821 AC: 1200 AN: 1461660 Hom.: 21 Cov.: 32 AF XY: 0.000678 AC XY: 493 AN XY: 727132

African (AFR) AF: 0.0320 AC: 1070 AN: 33464

American (AMR) AF: 0.000829 AC: 37 AN: 44652

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86224

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

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

European-Non Finnish (NFE) AF: 0.00000899 AC: 10 AN: 1111928

Other (OTH) AF: 0.00132 AC: 80 AN: 60388

GnomAD4 genome AF: 0.00780 AC: 1187 AN: 152266 Hom.: 15 Cov.: 32 AF XY: 0.00744 AC XY: 554 AN XY: 74448

African (AFR) AF: 0.0278 AC: 1155 AN: 41558

American (AMR) AF: 0.00163 AC: 25 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68014

Other (OTH) AF: 0.00284 AC: 6 AN: 2110

Alfa AF: 0.00272 Hom.: 1

Bravo AF: 0.00907

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	2.3
DANN	Benign	0.57
PhyloP100		-0.0080
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6
Mutation Taster		=100/0	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: rs74485823; hg19: chr3-47161806;