rs546522074

Variant names:

• chr4-1900823-C-A
• rs546522074
• NM_001042424.3:c.169C>A

Your query was ambiguous. Multiple possible variants found:

• chr4-1900823-C-A
• chr4-1900823-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001440899.1(NSD2):​c.-638C>A variant causes a 5 prime UTR premature start codon gain 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NSD2 NM_001440899.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.00
• 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=0.21012238).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001440899.1. 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.169C>A	p.Leu57Met	missense	Exon 2 of 22	NP_001035889.1	O96028-1
	NSD2	NM_001440899.1		c.-638C>A		5_prime_UTR_premature_start_codon_gain	Exon 2 of 21	NP_001427828.1
	NSD2	NM_001440900.1		c.-905C>A		5_prime_UTR_premature_start_codon_gain	Exon 2 of 23	NP_001427829.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NSD2	ENST00000508803.6	TSL:1 MANE Select	c.169C>A	p.Leu57Met	missense	Exon 2 of 22	ENSP00000423972.1	O96028-1
	NSD2	ENST00000382892.6	TSL:1	c.169C>A	p.Leu57Met	missense	Exon 3 of 23	ENSP00000372348.2	O96028-1
	NSD2	ENST00000382895.7	TSL:1	c.169C>A	p.Leu57Met	missense	Exon 4 of 24	ENSP00000372351.3	O96028-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251230 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T
Eigen	Uncertain	0.21
Eigen_PC	Benign	0.11
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.85	D
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.21	T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	2.0	M
PhyloP100		1.0
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.41	N
REVEL	Benign	0.27
Sift	Uncertain	0.011	D
Sift4G	Benign	0.23	T
Polyphen		0.96	D
Vest4		0.35
MutPred		0.22		Gain of glycosylation at S56 (P = 0.0376)
MVP		0.42
MPC		0.85
ClinPred		0.74	D
GERP RS		4.2
PromoterAI		-0.0054	Neutral
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6
Varity_R		0.10
gMVP		0.24
Mutation Taster		=82/18	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: rs546522074; hg19: chr4-1902550;