5-177257077-A-G
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Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 3P and 16B. PM1PP2BP4_StrongBP6_Very_StrongBS2
The NM_022455.5(NSD1):āc.4892A>Gā(p.Lys1631Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000712 in 1,614,138 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Likely benign (ā ā ).
Frequency
Genomes: š 0.00036 ( 0 hom., cov: 31)
Exomes š: 0.000041 ( 0 hom. )
Consequence
NSD1
NM_022455.5 missense
NM_022455.5 missense
Scores
6
11
Clinical Significance
Conservation
PhyloP100: 3.67
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 Benign. Variant got -13 ACMG points.
PM1
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_022455.5
PP2
Missense variant where missense usually causes diseases, NSD1
BP4
Computational evidence support a benign effect (MetaRNN=0.021259487).
BP6
Variant 5-177257077-A-G is Benign according to our data. Variant chr5-177257077-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 96061.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS2
High AC in GnomAd4 at 55 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NSD1 | NM_022455.5 | c.4892A>G | p.Lys1631Arg | missense_variant | 13/23 | ENST00000439151.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NSD1 | ENST00000439151.7 | c.4892A>G | p.Lys1631Arg | missense_variant | 13/23 | 1 | NM_022455.5 | P2 |
Frequencies
GnomAD3 genomes AF: 0.000362 AC: 55AN: 152144Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.0000875 AC: 22AN: 251466Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135908
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GnomAD4 exome AF: 0.0000410 AC: 60AN: 1461876Hom.: 0 Cov.: 32 AF XY: 0.0000426 AC XY: 31AN XY: 727244
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GnomAD4 genome AF: 0.000361 AC: 55AN: 152262Hom.: 0 Cov.: 31 AF XY: 0.000309 AC XY: 23AN XY: 74452
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Pathogenic:1Uncertain:1Benign:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Sotos syndrome Pathogenic:1Benign:3
Likely pathogenic, flagged submission | clinical testing | Genetic Services Laboratory, University of Chicago | Feb 08, 2013 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jul 29, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 15, 2021 | - - |
Benign, criteria provided, single submitter | clinical testing | Mendelics | Aug 22, 2023 | - - |
not provided Uncertain:1Benign:1
Benign, criteria provided, single submitter | clinical testing | GeneDx | Nov 18, 2020 | - - |
Uncertain significance, flagged submission | clinical testing | Eurofins Ntd Llc (ga) | Oct 10, 2013 | - - |
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 08, 2018 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
NSD1-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Mar 03, 2021 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;.
M_CAP
Benign
D
MetaRNN
Benign
T;T;T
MetaSVM
Uncertain
D
MutationTaster
Benign
N;N;N;N
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;N
REVEL
Uncertain
Sift
Benign
T;T;T
Sift4G
Benign
T;T;T
Polyphen
P;B;P
Vest4
MVP
MPC
0.67
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at