rs886038673

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP2

The NM_022455.5(NSD1):​c.2731C>A​(p.Leu911Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L911L) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

NSD1
NM_022455.5 missense

Scores

4
9
6

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.26
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 3 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.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
NSD1NM_022455.5 linkuse as main transcriptc.2731C>A p.Leu911Ile missense_variant 5/23 ENST00000439151.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
NSD1ENST00000439151.7 linkuse as main transcriptc.2731C>A p.Leu911Ile missense_variant 5/231 NM_022455.5 P2Q96L73-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
37
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.85
BayesDel_addAF
Pathogenic
0.18
D
BayesDel_noAF
Uncertain
0.020
CADD
Benign
22
DANN
Uncertain
0.99
DEOGEN2
Benign
0.22
.;T;.
Eigen
Benign
0.045
Eigen_PC
Benign
0.022
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Uncertain
0.90
D;D;.
M_CAP
Pathogenic
0.30
D
MetaRNN
Uncertain
0.42
T;T;T
MetaSVM
Uncertain
0.50
D
MutationAssessor
Benign
0.97
.;L;.
MutationTaster
Benign
0.97
N;N;N;N
PrimateAI
Uncertain
0.77
T
PROVEAN
Benign
-0.72
N;N;N
REVEL
Uncertain
0.52
Sift
Pathogenic
0.0
D;D;D
Sift4G
Uncertain
0.012
D;D;D
Polyphen
1.0
D;D;D
Vest4
0.51
MutPred
0.21
.;Gain of methylation at K915 (P = 0.0465);.;
MVP
0.59
MPC
0.37
ClinPred
0.70
D
GERP RS
1.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.21
gMVP
0.30

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: chr5-176638131; API