4-1900682-C-G

Variant names:

• chr4-1900682-C-G
• rs1328532362
• NM_001042424.3:c.28C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 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. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L10F) has been classified 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
• Publications: 1 publications found

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]

NSD2 Gene-Disease associations (from GenCC):

• Rauch-Steindl syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• syndromic intellectual disability

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• Wolf-Hirschhorn syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: Illumina
• neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13741654).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001042424.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NSD2	NM_001042424.3	MANE Select	c.28C>G	p.Leu10Val	missense	Exon 2 of 22	NP_001035889.1	O96028-1
	NSD2	NM_001440893.1		c.28C>G	p.Leu10Val	missense	Exon 2 of 22	NP_001427822.1
	NSD2	NM_001440892.1		c.28C>G	p.Leu10Val	missense	Exon 3 of 23	NP_001427821.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NSD2	ENST00000508803.6	TSL:1 MANE Select	c.28C>G	p.Leu10Val	missense	Exon 2 of 22	ENSP00000423972.1	O96028-1
	NSD2	ENST00000382892.6	TSL:1	c.28C>G	p.Leu10Val	missense	Exon 3 of 23	ENSP00000372348.2	O96028-1
	NSD2	ENST00000382895.7	TSL:1	c.28C>G	p.Leu10Val	missense	Exon 4 of 24	ENSP00000372351.3	O96028-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000409 AC: 1 AN: 244782 AF XY: 0.00

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 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

African (AFR) AF: 0.00 AC: 0 AN: 33114

American (AMR) AF: 0.00 AC: 0 AN: 43154

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25652

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39480

South Asian (SAS) AF: 0.00 AC: 0 AN: 84962

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53232

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5718

European-Non Finnish (NFE) AF: 9.06e-7 AC: 1 AN: 1104256

Other (OTH) AF: 0.00 AC: 0 AN: 59854

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.11
Eigen_PC	Benign	0.043
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.14	T
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Benign	1.6	L
PhyloP100		2.8
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.54	N
REVEL	Benign	0.082
Sift	Benign	0.078	T
Sift4G	Benign	0.48	T
Polyphen		0.049	B
Vest4		0.28
MutPred		0.14		Loss of catalytic residue at L10 (P = 0.0145)
MVP		0.44
MPC		0.35
ClinPred		0.23	T
GERP RS		4.8
PromoterAI		0.010	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.049
gMVP		0.15
Mutation Taster		=93/7	polymorphism

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

Other links and lift over

dbSNP: rs1328532362; hg19: chr4-1902409;