rs587784169

Positions:

• chr5-177282523-G-A
• chr5-177282523-G-C
• chr5-177282523-G-T

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The ENST00000439151.7(NSD1):​c.5951G>A​(p.Arg1984Gln) 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1984P) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NSD1 ENST00000439151.7 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 8.15

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]

ACMG classification

Verdict is Pathogenic. Variant got 19 ACMG points.

• PM1: In a domain SET (size 117) in uniprot entity NSD1_HUMAN there are 55 pathogenic changes around while only 1 benign (98%) in ENST00000439151.7
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-177282523-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 426653.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.978
• PP5: Variant 5-177282523-G-A is Pathogenic according to our data. Variant chr5-177282523-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 159390.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NSD1	NM_022455.5	c.5951G>A	p.Arg1984Gln	missense_variant	19/23	ENST00000439151.7	NP_071900.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NSD1	ENST00000439151.7	c.5951G>A	p.Arg1984Gln	missense_variant	19/23	1	NM_022455.5	ENSP00000395929	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Sotos syndrome Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 30, 2022	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1984 of the NSD1 protein (p.Arg1984Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Sotos syndrome (PMID: 12807965, 15942875, 16247291, 17561922, 17565729). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 159390). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt NSD1 protein function. Experimental studies have shown that this missense change affects NSD1 function (PMID: 21196496, 24412544, 27834868). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 19, 2024	Variant summary: NSD1 c.5951G>A (p.Arg1984Gln) results in a conservative amino acid change located in the SET domain (IPR001214) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251304 control chromosomes (gnomAD). c.5951G>A has been reported in the literature in individuals affected with Sotos Syndrome, including one de novo occurrence (Tatton-Brown_2005, Lu_2017). These data indicate that the variant is likely to be associated with disease. At least two publication report experimental evidence evaluating an impact on protein function and this variant results in completely lost its ability to methylate H3 (Qiao_2010, Kudithipudi_2014). The following publications have been ascertained in the context of this evaluation (PMID: 27834868, 24412544, 29142766, 21196496, 15942875). ClinVar contains an entry for this variant (Variation ID: 159390). Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Dec 13, 2021

Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21196496, 17565729, 24412544, 27834868, 16010675, 17561922, 15452385, 16247291, 12807965, 29142766) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.69	.;D;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D;.
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.5	.;M;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-3.6	D;D;D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.74
MutPred		0.92		.;Loss of loop (P = 0.0374);.;
MVP		0.99
MPC		2.8
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.92
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

Other links and lift over

dbSNP: rs587784169; hg19: chr5-176709524; COSMIC: COSV61784064; COSMIC: COSV61784064;