4-1900682-C-G

Position:

• chr4-1900682-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001042424.3(NSD2):​c.28C>G​(p.Leu10Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,449,422 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: NSD2 NM_001042424.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.81

Genes affected

NSD2 (HGNC:12766): (nuclear receptor binding SET domain protein 2) This gene encodes a protein that contains four domains present in other developmental proteins: a PWWP domain, an HMG box, a SET domain, and a PHD-type zinc finger. It is expressed ubiquitously in early development. Wolf-Hirschhorn syndrome (WHS) is a malformation syndrome associated with a hemizygous deletion of the distal short arm of chromosome 4. This gene maps to the 165 kb WHS critical region and has also been involved in the chromosomal translocation t(4;14)(p16.3;q32.3) in multiple myelomas. Alternative splicing of this gene results in multiple transcript variants encoding different isoforms. Some transcript variants are nonsense-mediated mRNA (NMD) decay candidates, hence not represented as reference sequences. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), NSD2. . Gene score misZ 3.8981 (greater than the threshold 3.09). Trascript score misZ 5.6522 (greater than threshold 3.09). GenCC has associacion of gene with Rauch-Steindl syndrome, syndromic intellectual disability, Wolf-Hirschhorn syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.13741654).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NSD2	NM_001042424.3	c.28C>G	p.Leu10Val	missense_variant	2/22	ENST00000508803.6	NP_001035889.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NSD2	ENST00000508803.6	c.28C>G	p.Leu10Val	missense_variant	2/22	1	NM_001042424.3	ENSP00000423972	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000409 AC: 1 AN: 244782 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 132194

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000548

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1449422 Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1 AN XY: 719300

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.06e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 23, 2021

The c.28C>G (p.L10V) alteration is located in exon 4 (coding exon 1) of the WHSC1 gene. This alteration results from a C to G substitution at nucleotide position 28, causing the leucine (L) at amino acid position 10 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	0.063
BayesDel_addAF	Benign	-0.019	T
BayesDel_noAF	Benign	-0.10
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Benign	0.093	T;.;.;.;T;T;.;T;.;T;.;.
Eigen	Benign	-0.11
Eigen_PC	Benign	0.043
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.82	.;T;.;T;.;T;T;.;.;T;T;T
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.14	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Benign	1.6	L;.;L;.;L;L;L;L;L;.;L;L
MutationTaster	Benign	0.94	N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.54	N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.082
Sift	Benign	0.078	T;D;D;D;T;T;D;T;D;D;D;D
Sift4G	Benign	0.48	T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.049	B;.;P;.;B;B;P;B;P;.;P;B
Vest4		0.28
MutPred		0.14		Loss of catalytic residue at L10 (P = 0.0145);Loss of catalytic residue at L10 (P = 0.0145);Loss of catalytic residue at L10 (P = 0.0145);Loss of catalytic residue at L10 (P = 0.0145);Loss of catalytic residue at L10 (P = 0.0145);Loss of catalytic residue at L10 (P = 0.0145);Loss of catalytic residue at L10 (P = 0.0145);Loss of catalytic residue at L10 (P = 0.0145);Loss of catalytic residue at L10 (P = 0.0145);Loss of catalytic residue at L10 (P = 0.0145);Loss of catalytic residue at L10 (P = 0.0145);Loss of catalytic residue at L10 (P = 0.0145);
MVP		0.44
MPC		0.35
ClinPred		0.23	T
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.049
gMVP		0.15

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

Other links and lift over

dbSNP: rs1328532362; hg19: chr4-1902409;