4-1900722-A-G

Variant names:

• chr4-1900722-A-G
• NM_001042424.3:c.68A>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001042424.3(NSD2):​c.68A>G​(p.Gln23Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,644 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: NSD2 NM_001042424.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.23

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 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NSD2	NM_001042424.3	c.68A>G	p.Gln23Arg	missense_variant	Exon 2 of 22	ENST00000508803.6	NP_001035889.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NSD2	ENST00000508803.6	c.68A>G	p.Gln23Arg	missense_variant	Exon 2 of 22	1	NM_001042424.3	ENSP00000423972.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461644 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727138

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: 8.99e-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

Apr 29, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.68A>G (p.Q23R) alteration is located in exon 4 (coding exon 1) of the NSD2 (WHSC1) gene. This alteration results from a A to G substitution at nucleotide position 68, causing the glutamine (Q) at amino acid position 23 to be replaced by an arginine (R). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. 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	0.15
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	T;.;.;.;T;T;.;T;.;T;.;.
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.78	.;T;.;D;.;D;D;.;.;D;D;D
M_CAP	Pathogenic	0.35	D
MetaRNN	Uncertain	0.58	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	2.0	M;.;M;.;M;M;M;M;M;.;M;M
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.2	N;D;N;D;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.42
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;D;D
Sift4G	Benign	0.29	T;D;D;D;T;T;D;T;D;D;D;D
Polyphen		0.99	D;.;D;.;D;D;D;D;D;.;D;D
Vest4		0.63
MutPred		0.23		Gain of MoRF binding (P = 0.019);Gain of MoRF binding (P = 0.019);Gain of MoRF binding (P = 0.019);Gain of MoRF binding (P = 0.019);Gain of MoRF binding (P = 0.019);Gain of MoRF binding (P = 0.019);Gain of MoRF binding (P = 0.019);Gain of MoRF binding (P = 0.019);Gain of MoRF binding (P = 0.019);Gain of MoRF binding (P = 0.019);Gain of MoRF binding (P = 0.019);Gain of MoRF binding (P = 0.019);
MVP		0.97
MPC		0.94
ClinPred		0.85	D
GERP RS		5.6
Varity_R		0.36
gMVP		0.66

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr4-1902449;