Variant 8-38279582-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_023034.2(NSD3):c.3718G>A(p.Asp1240Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,846 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

NSD3
NM_023034.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.91

Variant links:

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 links:

NSD3 (HGNC:):

NSD3 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.813

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NSD3	NM_023034.2 linkuse as main transcript	c.3718G>A	p.Asp1240Asn	missense_variant	21/24	ENST00000317025.13	NP_075447.1	Q9BZ95-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
NSD3	ENST00000317025.13 linkuse as main transcript	c.3718G>A	p.Asp1240Asn	missense_variant	21/24	1	NM_023034.2	ENSP00000313983.7	Q9BZ95-1
NSD3	ENST00000527502.5 linkuse as main transcript	c.3685G>A	p.Asp1229Asn	missense_variant	21/24	1		ENSP00000434730.1	Q9BZ95-5
NSD3	ENST00000433384.6 linkuse as main transcript	c.3571G>A	p.Asp1191Asn	missense_variant	20/23	1		ENSP00000393284.2	Q9BZ95-2
NSD3	ENST00000528828.1 linkuse as main transcript	n.629G>A		non_coding_transcript_exon_variant	1/4	1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461846

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727222

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

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:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 07, 2024

The c.3718G>A (p.D1240N) alteration is located in exon 21 (coding exon 20) of the WHSC1L1 gene. This alteration results from a G to A substitution at nucleotide position 3718, causing the aspartic acid (D) at amino acid position 1240 to be replaced by an asparagine (N). 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

Pathogenic

0.68

BayesDel_addAF

Benign

0.011

BayesDel_noAF

Benign

-0.22

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.26

T;.;.

Eigen

Pathogenic

0.90

Eigen_PC

Pathogenic

0.88

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.98

D;D;D

M_CAP

Uncertain

0.099

MetaRNN

Pathogenic

0.81

D;D;D

MetaSVM

Uncertain

0.42

MutationAssessor

Uncertain

2.4

M;.;.

PrimateAI

Pathogenic

0.86

PROVEAN

Pathogenic

-4.5

D;D;D

REVEL

Uncertain

0.61

Sift

Uncertain

0.0010

D;D;D

Sift4G

Uncertain

0.0030

D;D;D

Polyphen

1.0

D;D;.

Vest4

0.75

MutPred

0.55

Loss of stability (P = 0.1356);.;.;

MVP

0.73

MPC

2.3

ClinPred

0.99

GERP RS

5.7

Varity_R

0.78

gMVP

0.80

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over