rs1554208207

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_022455.5(NSD1):​c.8018C>G​(p.Pro2673Arg) variant causes a missense 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. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 32)

Consequence

NSD1
NM_022455.5 missense

Scores

5
6
8

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 3.02
Variant links:
Genes affected
NSD1 (HGNC:14234): (nuclear receptor binding SET domain protein 1) This gene encodes a protein containing a SET domain, 2 LXXLL motifs, 3 nuclear translocation signals (NLSs), 4 plant homeodomain (PHD) finger regions, and a proline-rich region. The encoded protein enhances androgen receptor (AR) transactivation, and this enhancement can be increased further in the presence of other androgen receptor associated coregulators. This protein may act as a nucleus-localized, basic transcriptional factor and also as a bifunctional transcriptional regulator. Mutations of this gene have been associated with Sotos syndrome and Weaver syndrome. One version of childhood acute myeloid leukemia is the result of a cryptic translocation with the breakpoints occurring within nuclear receptor-binding Su-var, enhancer of zeste, and trithorax domain protein 1 on chromosome 5 and nucleoporin, 98-kd on chromosome 11. Multiple transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Sep 2018]

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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 in gene, where missense usually causes diseases (based on misZ statistic), NSD1. . Gene score misZ 3.4113 (greater than the threshold 3.09). Trascript score misZ 5.7368 (greater than threshold 3.09). GenCC has associacion of gene with Beckwith-Wiedemann syndrome, Weaver syndrome, Sotos syndrome 1, Sotos syndrome.
BP4
Computational evidence support a benign effect (MetaRNN=0.21212304).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
NSD1NM_022455.5 linkuse as main transcriptc.8018C>G p.Pro2673Arg missense_variant 23/23 ENST00000439151.7 NP_071900.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
NSD1ENST00000439151.7 linkuse as main transcriptc.8018C>G p.Pro2673Arg missense_variant 23/231 NM_022455.5 ENSP00000395929 P2Q96L73-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
34
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpMay 22, 2024Variant summary: NSD1 c.8018C>G (p.Pro2673Arg) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251418 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.8018C>G in individuals affected with Sotos Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 524714). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Sotos syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpSep 01, 2021This sequence change replaces proline with arginine at codon 2673 of the NSD1 protein (p.Pro2673Arg). The proline residue is weakly conserved and there is a moderate physicochemical difference between proline and arginine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with NSD1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.13
BayesDel_addAF
Pathogenic
0.20
D
BayesDel_noAF
Uncertain
0.050
CADD
Benign
23
DANN
Uncertain
1.0
DEOGEN2
Benign
0.15
.;T;.
Eigen
Uncertain
0.36
Eigen_PC
Uncertain
0.44
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Benign
0.84
T;T;.
M_CAP
Uncertain
0.11
D
MetaRNN
Benign
0.21
T;T;T
MetaSVM
Pathogenic
0.94
D
MutationAssessor
Benign
0.55
.;N;.
MutationTaster
Benign
0.95
D;D;D;D
PrimateAI
Benign
0.42
T
PROVEAN
Benign
-1.8
N;N;N
REVEL
Uncertain
0.46
Sift
Pathogenic
0.0
D;D;D
Sift4G
Pathogenic
0.0
D;D;D
Polyphen
0.85
P;P;P
Vest4
0.15
MutPred
0.23
.;Gain of MoRF binding (P = 0.055);.;
MVP
0.55
MPC
0.15
ClinPred
0.58
D
GERP RS
5.0
Varity_R
0.32
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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1554208207; hg19: chr5-176722387; API