8-38290632-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Moderate BP6_Very_Strong BS2

The NM_023034.2(NSD3):c.2961C>T(p.Asn987=) variant causes a synonymous change. The variant allele was found at a frequency of 0.000614 in 1,613,962 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00098 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00058 (7 hom.)
• Consequence: NSD3 NM_023034.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.72

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 8-38290632-G-A is Benign according to our data. Variant chr8-38290632-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 713975.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 148 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NSD3	NM_023034.2	c.2961C>T	p.Asn987=	synonymous_variant	17/24	ENST00000317025.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NSD3	ENST00000317025.13	c.2961C>T	p.Asn987=	synonymous_variant	17/24	1	NM_023034.2	P4
NSD3	ENST00000527502.5	c.2961C>T	p.Asn987=	synonymous_variant	17/24	1
NSD3	ENST00000433384.6	c.2814C>T	p.Asn938=	synonymous_variant	16/23	1		A1
NSD3	ENST00000526050.1	n.117C>T		non_coding_transcript_exon_variant	1/2	3

Frequencies

GnomAD3 genomes AF: 0.000973 AC: 148 AN: 152180 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000555

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00733

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.00240 AC: 599 AN: 249270 Hom.: 7 AF XY: 0.00183 AC XY: 247 AN XY: 135236

Gnomad AFR exome AF: 0.000452

Gnomad AMR exome AF: 0.0161

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00111

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000266

Gnomad OTH exome AF: 0.00215

GnomAD4 exome AF: 0.000576 AC: 842 AN: 1461664 Hom.: 7 Cov.: 31 AF XY: 0.000509 AC XY: 370 AN XY: 727142

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.0157

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00212

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000135

Gnomad4 OTH exome AF: 0.000580

GnomAD4 genome AF: 0.000978 AC: 149 AN: 152298 Hom.: 2 Cov.: 32 AF XY: 0.000860 AC XY: 64 AN XY: 74456

Gnomad4 AFR AF: 0.000553

Gnomad4 AMR AF: 0.00739

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00135

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000474 Hom.: 0

Bravo AF: 0.00155

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jun 22, 2018

- -

NSD3-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 21, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
Cadd	Benign	6.8
Dann	Benign	0.68
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs146132494; hg19: chr8-38148150;