4-1900692-A-G

Position:

• chr4-1900692-A-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.38A>G​(p.Gln13Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,457,046 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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: 0.0000021 (0 hom.)
• Consequence: NSD2 NM_001042424.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.769

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=0.07872).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NSD2	NM_001042424.3	c.38A>G	p.Gln13Arg	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.38A>G	p.Gln13Arg	missense_variant	2/22	1	NM_001042424.3	ENSP00000423972	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1457046 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 724306

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Uncertain	0.044	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	12
DANN	Benign	0.94
DEOGEN2	Benign	0.11	T;.;.;.;T;T;.;T;.;T;.;.
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.61	.;T;.;T;.;T;T;.;.;T;T;T
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.079	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Benign	1.2	L;.;L;.;L;L;L;L;L;.;L;L
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.85	N;D;N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.060
Sift	Benign	0.080	T;D;D;D;T;T;D;T;D;D;D;D
Sift4G	Benign	0.26	T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.20	B;.;B;.;B;B;B;B;B;.;B;B
Vest4		0.13
MutPred		0.20		Gain of MoRF binding (P = 0.0103);Gain of MoRF binding (P = 0.0103);Gain of MoRF binding (P = 0.0103);Gain of MoRF binding (P = 0.0103);Gain of MoRF binding (P = 0.0103);Gain of MoRF binding (P = 0.0103);Gain of MoRF binding (P = 0.0103);Gain of MoRF binding (P = 0.0103);Gain of MoRF binding (P = 0.0103);Gain of MoRF binding (P = 0.0103);Gain of MoRF binding (P = 0.0103);Gain of MoRF binding (P = 0.0103);
MVP		0.30
MPC		0.32
ClinPred		0.096	T
GERP RS		0.034
Varity_R		0.054
gMVP		0.13

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: chr4-1902419;