8-38279537-T-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP3 BP6_Moderate BS2

The NM_023034.2(NSD3):c.3760+3A>G variant causes a splice donor region, intron change. The variant allele was found at a frequency of 0.000315 in 1,613,626 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 Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: NSD3 NM_023034.2 splice_donor_region, intron
• Scores: Splicing: ADA: 0.9956
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.72

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 Likely_benign. Variant got -5 ACMG points.

• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• BP6: Variant 8-38279537-T-C is Benign according to our data. Variant chr8-38279537-T-C is described in ClinVar as [Benign]. Clinvar id is 776321.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 237 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NSD3	NM_023034.2	c.3760+3A>G		splice_donor_region_variant, intron_variant		ENST00000317025.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NSD3	ENST00000317025.13	c.3760+3A>G		splice_donor_region_variant, intron_variant		1	NM_023034.2	P4
NSD3	ENST00000433384.6	c.3613+3A>G		splice_donor_region_variant, intron_variant		1		A1
NSD3	ENST00000527502.5	c.3727+3A>G		splice_donor_region_variant, intron_variant		1
NSD3	ENST00000528828.1	n.671+3A>G		splice_donor_region_variant, intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.00156 AC: 237 AN: 152214 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00548

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000361 AC: 90 AN: 249414 Hom.: 0 AF XY: 0.000296 AC XY: 40 AN XY: 135332

Gnomad AFR exome AF: 0.00504

Gnomad AMR exome AF: 0.000261

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000183 AC: 268 AN: 1461294 Hom.: 0 Cov.: 30 AF XY: 0.000161 AC XY: 117 AN XY: 726888

Gnomad4 AFR exome AF: 0.00598

Gnomad4 AMR exome AF: 0.000291

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000135

Gnomad4 OTH exome AF: 0.000563

GnomAD4 genome AF: 0.00158 AC: 240 AN: 152332 Hom.: 0 Cov.: 32 AF XY: 0.00165 AC XY: 123 AN XY: 74488

Gnomad4 AFR AF: 0.00553

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000964 Hom.: 0

Bravo AF: 0.00173

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jun 26, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
Cadd	Benign	19
Dann	Benign	0.93

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.86
SpliceAI score (max)		0.020		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: rs190676759; hg19: chr8-38137055;