chr4-1900827-A-C

Position:

• chr4-1900827-A-C

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.173A>C​(p.Gln58Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 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)
• Consequence: NSD2 NM_001042424.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.16

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=0.1731976).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NSD2	NM_001042424.3	c.173A>C	p.Gln58Pro	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.173A>C	p.Gln58Pro	missense_variant	2/22	1	NM_001042424.3	ENSP00000423972	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.27	T;.;.;T;T;.;T;.;T;.;.
Eigen	Benign	-0.058
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.80	.;.;T;.;T;T;.;.;T;T;T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.17	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.38	D
MutationAssessor	Benign	1.6	L;L;.;L;L;L;L;L;.;L;L
MutationTaster	Benign	0.95	D;D;D;D;D;D;D;D;D
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.6	N;N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.12
Sift	Benign	0.053	T;D;T;T;T;D;T;D;D;D;D
Sift4G	Benign	0.41	T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.0080	B;B;.;B;B;B;B;B;.;B;B
Vest4		0.39
MutPred		0.30		Gain of loop (P = 0.002);Gain of loop (P = 0.002);Gain of loop (P = 0.002);Gain of loop (P = 0.002);Gain of loop (P = 0.002);Gain of loop (P = 0.002);Gain of loop (P = 0.002);Gain of loop (P = 0.002);Gain of loop (P = 0.002);Gain of loop (P = 0.002);Gain of loop (P = 0.002);
MVP		0.31
MPC		0.37
ClinPred		0.51	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.19
gMVP		0.57

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: chr4-1902554;