rs587784135

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PM5PP2PP3_StrongPP5_Moderate

The NM_022455.5(NSD1):​c.5021G>A​(p.Cys1674Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C1674W) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

NSD1
NM_022455.5 missense

Scores

14
4
1

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 10.0
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 Pathogenic. Variant got 11 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
PP2
Missense variant in the NSD1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 137 curated pathogenic missense variants (we use a threshold of 10). The gene has 153 curated benign missense variants. Gene score misZ: 3.4113 (above the threshold of 3.09). Trascript score misZ: 5.7368 (above the threshold of 3.09). GenCC associations: The gene is linked to Beckwith-Wiedemann syndrome, Weaver syndrome, Sotos syndrome 1, Sotos syndrome.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.974
PP5
Variant 5-177260043-G-A is Pathogenic according to our data. Variant chr5-177260043-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 159356.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NSD1NM_022455.5 linkc.5021G>A p.Cys1674Tyr missense_variant Exon 14 of 23 ENST00000439151.7 NP_071900.2 Q96L73-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
NSD1ENST00000439151.7 linkc.5021G>A p.Cys1674Tyr missense_variant Exon 14 of 23 1 NM_022455.5 ENSP00000395929.2 Q96L73-1

Frequencies

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

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Sotos syndrome Pathogenic:1
May 31, 2013
Genetic Services Laboratory, University of Chicago
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.56
D
BayesDel_noAF
Pathogenic
0.57
CADD
Pathogenic
31
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.72
.;D;.
Eigen
Pathogenic
1.0
Eigen_PC
Pathogenic
0.99
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
1.0
D;D;.
M_CAP
Pathogenic
0.62
D
MetaRNN
Pathogenic
0.97
D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
3.6
.;H;.
PrimateAI
Pathogenic
0.91
D
PROVEAN
Pathogenic
-10
D;D;D
REVEL
Pathogenic
0.95
Sift
Uncertain
0.0010
D;D;D
Sift4G
Uncertain
0.0020
D;D;D
Polyphen
1.0
D;D;D
Vest4
0.96
MutPred
0.77
.;Loss of catalytic residue at L1675 (P = 0.0292);.;
MVP
0.99
MPC
3.5
ClinPred
1.0
D
GERP RS
5.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.2
Varity_R
0.93
gMVP
0.98

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: rs587784135; hg19: chr5-176687044; API