8-38304631-T-C

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP2 BP4_Moderate

The NM_023034.2(NSD3):c.2567A>G(p.Asn856Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000123 in 1,461,330 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: NSD3 NM_023034.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.49

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]

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PP2: Missense variant where missense usually causes diseases, NSD3
• BP4: Computational evidence support a benign effect (MetaRNN=0.0997287).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NSD3	NM_023034.2	c.2567A>G	p.Asn856Ser	missense_variant	14/24	ENST00000317025.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NSD3	ENST00000317025.13	c.2567A>G	p.Asn856Ser	missense_variant	14/24	1	NM_023034.2	P4
NSD3	ENST00000527502.5	c.2567A>G	p.Asn856Ser	missense_variant	14/24	1
NSD3	ENST00000433384.6	c.2567A>G	p.Asn856Ser	missense_variant	14/23	1		A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000402 AC: 1 AN: 248920 Hom.: 0 AF XY: 0.00000740 AC XY: 1 AN XY: 135094

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000884

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000123 AC: 18 AN: 1461330 Hom.: 0 Cov.: 31 AF XY: 0.0000151 AC XY: 11 AN XY: 726978

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000162

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.000224 Hom.: 0

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 25, 2023

The c.2567A>G (p.N856S) alteration is located in exon 14 (coding exon 13) of the WHSC1L1 gene. This alteration results from a A to G substitution at nucleotide position 2567, causing the asparagine (N) at amino acid position 856 to be replaced by a serine (S). 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	Benign	0.061
BayesDel_addAF	Benign	-0.033	T
BayesDel_noAF	Benign	-0.29
Cadd	Benign	5.5
Dann	Benign	0.73
DEOGEN2	Benign	0.20	T;.;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.99
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.78	T;T;T
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.10	T;T;T
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	1.3	L;L;L
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.25	T
PROVEAN	Uncertain	-2.8	D;D;D
REVEL	Benign	0.23
Sift	Benign	0.38	T;T;T
Sift4G	Benign	0.096	T;T;T
Polyphen		0.0	B;B;.
Vest4		0.19
MutPred		0.36		Gain of phosphorylation at N856 (P = 0.0302);Gain of phosphorylation at N856 (P = 0.0302);Gain of phosphorylation at N856 (P = 0.0302);
MVP		0.12
MPC		0.35
ClinPred		0.077	T
GERP RS		-3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.067
gMVP		0.19

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs1217505756; hg19: chr8-38162149;