8-38275720-G-A

Position:

• chr8-38275720-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_023034.2(NSD3):​c.4235C>T​(p.Ala1412Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NSD3 NM_023034.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.66

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.096016586).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NSD3	NM_023034.2	c.4235C>T	p.Ala1412Val	missense_variant	24/24	ENST00000317025.13	NP_075447.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NSD3	ENST00000317025.13	c.4235C>T	p.Ala1412Val	missense_variant	24/24	1	NM_023034.2	ENSP00000313983.7
NSD3	ENST00000527502.5	c.4202C>T	p.Ala1401Val	missense_variant	24/24	1		ENSP00000434730.1
NSD3	ENST00000433384.6	c.4088C>T	p.Ala1363Val	missense_variant	23/23	1		ENSP00000393284.2
NSD3	ENST00000528828.1	n.1146C>T		non_coding_transcript_exon_variant	4/4	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Nov 13, 2024

The c.4235C>T (p.A1412V) alteration is located in exon 24 (coding exon 23) of the WHSC1L1 gene. This alteration results from a C to T substitution at nucleotide position 4235, causing the alanine (A) at amino acid position 1412 to be replaced by a valine (V). 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	0.078
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.033	T;.;.
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.61	D
LIST_S2	Uncertain	0.88	D;D;D
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.096	T;T;T
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	1.0	L;.;.
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-2.1	N;N;N
REVEL	Benign	0.13
Sift	Benign	0.098	T;T;T
Sift4G	Benign	0.32	T;T;T
Polyphen		0.0060	B;B;.
Vest4		0.14
MutPred		0.38		Gain of catalytic residue at A1412 (P = 0.057);.;.;
MVP		0.32
MPC		1.4
ClinPred		0.24	T
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.058
gMVP		0.56

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-38133238;