4-1978885-G-T

Variant names:

• chr4-1978885-G-T
• rs1553881444
• NM_001042424.3:c.4074G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001440893.1(NSD2):​c.4173G>T​(p.Trp1391Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000000702 in 1,425,002 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: NSD2 NM_001440893.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.13
• Publications: 0 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001440893.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NSD2	NM_001042424.3	MANE Select	c.4074G>T	p.Trp1358Cys	missense	Exon 22 of 22	NP_001035889.1
	NSD2	NM_001440893.1		c.4173G>T	p.Trp1391Cys	missense	Exon 22 of 22	NP_001427822.1
	NSD2	NM_001440892.1		c.4074G>T	p.Trp1358Cys	missense	Exon 23 of 23	NP_001427821.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NSD2	ENST00000508803.6	TSL:1 MANE Select	c.4074G>T	p.Trp1358Cys	missense	Exon 22 of 22	ENSP00000423972.1
	NSD2	ENST00000382892.6	TSL:1	c.4074G>T	p.Trp1358Cys	missense	Exon 23 of 23	ENSP00000372348.2
	NSD2	ENST00000382895.7	TSL:1	c.4074G>T	p.Trp1358Cys	missense	Exon 24 of 24	ENSP00000372351.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.02e-7 AC: 1 AN: 1425002 Hom.: 0 Cov.: 31 AF XY: 0.00000142 AC XY: 1 AN XY: 704210

African (AFR) AF: 0.00 AC: 0 AN: 32504

American (AMR) AF: 0.00 AC: 0 AN: 41090

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24512

East Asian (EAS) AF: 0.00 AC: 0 AN: 38646

South Asian (SAS) AF: 0.00 AC: 0 AN: 82134

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51116

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5402

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1091026

Other (OTH) AF: 0.0000171 AC: 1 AN: 58572

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.14	T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.76	T
M_CAP	Pathogenic	0.50	D
MetaRNN	Uncertain	0.49	T
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	1.8	L
PhyloP100		4.1
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.57
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.52
MutPred		0.47		Gain of glycosylation at T1362 (P = 3e-04)
MVP		0.27
MPC		0.0091
ClinPred		0.91	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.25
gMVP		0.37
Mutation Taster		=76/24	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: rs1553881444; hg19: chr4-1980612;