chr3-47120374-A-G

Position:

• chr3-47120374-A-G

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 1P and 12B. PP2 BP4_Moderate BP6_Moderate BS1 BS2

The NM_014159.7(SETD2):​c.4262T>C​(p.Leu1421Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000281 in 1,460,640 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000028 (0 hom.)
• Consequence: SETD2 NM_014159.7 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1 O:1
• Conservation: PhyloP100: 1.74

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]

ACMG classification

Verdict is Benign. Variant got -11 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SETD2. . Gene score misZ 3.0459 (greater than the threshold 3.09). Trascript score misZ 4.1385 (greater than threshold 3.09). GenCC has associacion of gene with SETD2-related neurodevelopmental disorder without or with macrocephaly/overgrowth, Luscan-Lumish syndrome, Rabin-Pappas syndrome, SETD2-related microcephaly-severe intellectual disability-multiple congenital anomalies syndrome, Sotos syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.14987975).
• BP6: Variant 3-47120374-A-G is Benign according to our data. Variant chr3-47120374-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 135240.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.0000281 (41/1460640) while in subpopulation SAS AF= 0.000395 (34/86046). AF 95% confidence interval is 0.000291. There are 0 homozygotes in gnomad4_exome. There are 27 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAdExome4 at 41 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SETD2	NM_014159.7	c.4262T>C	p.Leu1421Pro	missense_variant	3/21	ENST00000409792.4	NP_054878.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SETD2	ENST00000409792.4	c.4262T>C	p.Leu1421Pro	missense_variant	3/21	5	NM_014159.7	ENSP00000386759	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000601 AC: 15 AN: 249792 Hom.: 0 AF XY: 0.0000741 AC XY: 10 AN XY: 135036

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000546

Gnomad SAS exome AF: 0.000395

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000330

GnomAD4 exome AF: 0.0000281 AC: 41 AN: 1460640 Hom.: 0 Cov.: 32 AF XY: 0.0000372 AC XY: 27 AN XY: 726620

Gnomad4 AFR exome AF: 0.0000300

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000395

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000829

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.0000659 AC: 8

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 12, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not specified Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.075	T
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.084	T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.58	T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-0.55	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	0.87	N
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.97	N
REVEL	Uncertain	0.48
Sift	Uncertain	0.017	D
Sift4G	Benign	0.21	T
Polyphen		0.0	B
Vest4		0.68
MutPred		0.15		Gain of glycosylation at S1417 (P = 0.0011);
MVP		0.94
MPC		0.42
ClinPred		0.029	T
GERP RS		4.0
Varity_R		0.28
gMVP		0.29

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

Publications

LitVar

Other links and lift over

dbSNP: rs587778677; hg19: chr3-47161864;