NM_014159.7:c.4121G>A

Variant names:

• chr3-47120515-C-T
• rs762222123
• NM_014159.7:c.4121G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_014159.7(SETD2):​c.4121G>A​(p.Ser1374Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,652 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: SETD2 NM_014159.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.73
• 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

ENSG00000296084 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.39571893).
• BS2: High AC in GnomAdExome4 at 6 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.4121G>A	p.Ser1374Asn	missense	Exon 3 of 21	NP_054878.5
	SETD2	NM_001349370.3		c.3989G>A	p.Ser1330Asn	missense	Exon 2 of 20	NP_001336299.1
	SETD2	NR_146158.3		n.4310G>A		non_coding_transcript_exon	Exon 3 of 22

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SETD2	ENST00000409792.4	TSL:5 MANE Select	c.4121G>A	p.Ser1374Asn	missense	Exon 3 of 21	ENSP00000386759.3
	SETD2	ENST00000330022.11	TSL:1	n.3734G>A		non_coding_transcript_exon	Exon 1 of 19	ENSP00000332415.7
	SETD2	ENST00000952253.1		c.4121G>A	p.Ser1374Asn	missense	Exon 3 of 20	ENSP00000622312.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000798 AC: 2 AN: 250482 AF XY: 0.00

Gnomad AFR exome AF: 0.0000630

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461652 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 727166

African (AFR) AF: 0.0000598 AC: 2 AN: 33418

American (AMR) AF: 0.00 AC: 0 AN: 44656

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111952

Other (OTH) AF: 0.00 AC: 0 AN: 60372

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Luscan-Lumish syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Benign	-0.0027	T
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.87	D
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.40	T
MetaSVM	Pathogenic	0.83	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		7.7
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.7	N
REVEL	Uncertain	0.38
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.040	D
Polyphen		1.0	D
Vest4		0.36
MutPred		0.20		Gain of sheet (P = 0.0061)
MVP		0.88
MPC		0.88
ClinPred		0.86	D
GERP RS		5.3
Varity_R		0.64
gMVP		0.50
Mutation Taster		=24/76	disease causing

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: rs762222123; hg19: chr3-47162005;