8-38276500-A-G

Position:

• chr8-38276500-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_023034.2(NSD3):​c.3868T>C​(p.Ser1290Pro) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: NSD3 NM_023034.2 missense, splice_region
• Scores: Splicing: ADA: 0.00008273
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.22

Genes affected

NSD3 (HGNC:12767): (nuclear receptor binding SET domain protein 3) This gene is related to the Wolf-Hirschhorn syndrome candidate-1 gene and encodes a protein with PWWP (proline-tryptophan-tryptophan-proline) domains. This protein methylates histone H3 at lysine residues 4 and 27, which represses gene transcription. Two alternatively spliced variants have been described. [provided by RefSeq, May 2015]

NSD3 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18300372).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NSD3	NM_023034.2	c.3868T>C	p.Ser1290Pro	missense_variant, splice_region_variant	23/24	ENST00000317025.13	NP_075447.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NSD3	ENST00000317025.13	c.3868T>C	p.Ser1290Pro	missense_variant, splice_region_variant	23/24	1	NM_023034.2	ENSP00000313983.7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 19, 2024

The c.3868T>C (p.S1290P) alteration is located in exon 23 (coding exon 22) of the WHSC1L1 gene. This alteration results from a T to C substitution at nucleotide position 3868, causing the serine (S) at amino acid position 1290 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Uncertain	0.066	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.042	T;.;.
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.13
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.57	T;T;T
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.18	T;T;T
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Benign	1.4	L;.;.
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-2.7	D;D;D
REVEL	Uncertain	0.32
Sift	Benign	0.048	D;T;T
Sift4G	Benign	0.11	T;T;T
Polyphen		0.77	P;P;.
Vest4		0.15
MutPred		0.20		Loss of phosphorylation at S1290 (P = 0.0256);.;.;
MVP		0.75
MPC		1.9
ClinPred		0.75	D
GERP RS		-0.38
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.13
gMVP		0.54

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000083
dbscSNV1_RF	Benign	0.060
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-38134018;