8-38276298-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_023034.2(NSD3):c.4070A>G(p.Tyr1357Cys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,756 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: NSD3 NM_023034.2 missense, splice_region
• Scores: Splicing: ADA: 0.003288
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.34

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]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, NSD3
• BP4: Computational evidence support a benign effect (MetaRNN=0.2917304).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NSD3	NM_023034.2	c.4070A>G	p.Tyr1357Cys	missense_variant, splice_region_variant	23/24	ENST00000317025.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NSD3	ENST00000317025.13	c.4070A>G	p.Tyr1357Cys	missense_variant, splice_region_variant	23/24	1	NM_023034.2	P4
	ENST00000529325.1	n.37-163T>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461756 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727164

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

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

Dec 18, 2023

The c.4070A>G (p.Y1357C) alteration is located in exon 23 (coding exon 22) of the WHSC1L1 gene. This alteration results from a A to G substitution at nucleotide position 4070, causing the tyrosine (Y) at amino acid position 1357 to be replaced by a cysteine (C). 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	0.12
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.17	T;.;.
Eigen	Benign	0.061
Eigen_PC	Benign	0.021
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.85	T;T;T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.29	T;T;T
MetaSVM	Uncertain	0.45	D
MutationAssessor	Benign	1.9	L;.;.
MutationTaster	Benign	0.71	N;N;N
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-2.2	N;N;N
REVEL	Uncertain	0.53
Sift	Benign	0.073	T;T;T
Sift4G	Benign	0.070	T;T;T
Polyphen		0.97	D;D;.
Vest4		0.33
MutPred		0.49		Loss of solvent accessibility (P = 0.0329);.;.;
MVP		0.14
MPC		1.4
ClinPred		0.71	D
GERP RS		2.9
Varity_R		0.25
gMVP		0.70

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0033
dbscSNV1_RF	Benign	0.040
SpliceAI score (max)		0.010		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: chr8-38133816;