4-1900863-C-A
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Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate
The NM_001042424.3(NSD2):c.209C>A(p.Ala70Asp) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,214 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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
NM_001042424.3 missense
Scores
2
9
7
Clinical Significance
Conservation
PhyloP100: 3.80
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 1 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant where missense usually causes diseases, NSD2
BP4
Computational evidence support a benign effect (MetaRNN=0.26118982).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NSD2 | NM_001042424.3 | c.209C>A | p.Ala70Asp | missense_variant | 2/22 | ENST00000508803.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NSD2 | ENST00000508803.6 | c.209C>A | p.Ala70Asp | missense_variant | 2/22 | 1 | NM_001042424.3 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
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32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 250952Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135642
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GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461214Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 726846
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GnomAD4 genome Cov.: 32
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32
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 10, 2023 | The c.209C>A (p.A70D) alteration is located in exon 4 (coding exon 1) of the WHSC1 gene. This alteration results from a C to A substitution at nucleotide position 209, causing the alanine (A) at amino acid position 70 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T;.;.;T;T;.;T;.;T;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Pathogenic
D
MutationAssessor
Benign
L;L;.;L;L;L;L;L;.;L;L
MutationTaster
Benign
D;D;D;D;D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;N;N;N;N;N;N;N;N;N
REVEL
Uncertain
Sift
Uncertain
D;D;D;D;D;D;D;D;D;D;D
Sift4G
Benign
T;T;D;T;T;T;T;T;T;T;T
Polyphen
P;D;.;P;P;D;P;D;.;D;D
Vest4
MutPred
Gain of relative solvent accessibility (P = 0.0082);Gain of relative solvent accessibility (P = 0.0082);Gain of relative solvent accessibility (P = 0.0082);Gain of relative solvent accessibility (P = 0.0082);Gain of relative solvent accessibility (P = 0.0082);Gain of relative solvent accessibility (P = 0.0082);Gain of relative solvent accessibility (P = 0.0082);Gain of relative solvent accessibility (P = 0.0082);Gain of relative solvent accessibility (P = 0.0082);Gain of relative solvent accessibility (P = 0.0082);Gain of relative solvent accessibility (P = 0.0082);
MVP
MPC
0.80
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
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Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at