5-177283827-G-A

Position:

• chr5-177283827-G-A

Variant summary

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

The NM_022455.5(NSD1):​c.6050G>A​(p.Arg2017Gln) 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. R2017W) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NSD1 NM_022455.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 9.95

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]

NSD1 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 19 ACMG points.

• PM1: In a domain SET (size 117) in uniprot entity NSD1_HUMAN there are 17 pathogenic changes around while only 0 benign (100%) in NM_022455.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-177283826-C-T is described in Lovd as [Pathogenic].
• 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, 0.99
• PP5: Variant 5-177283827-G-A is Pathogenic according to our data. Variant chr5-177283827-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 159398.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-177283827-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NSD1	NM_022455.5	c.6050G>A	p.Arg2017Gln	missense_variant	20/23	ENST00000439151.7	NP_071900.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NSD1	ENST00000439151.7	c.6050G>A	p.Arg2017Gln	missense_variant	20/23	1	NM_022455.5	ENSP00000395929.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Sotos syndrome Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	May 18, 2022	PM1, PM2, PM5, PP2, PP3, PP5 -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 26, 2021	This sequence change replaces arginine with glutamine at codon 2017 of the NSD1 protein (p.Arg2017Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with Sotos syndrome (PMID: 17565729, 27834868). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 159398). 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: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects NSD1 function (PMID: 21196496). This variant disrupts the p.Arg2017 amino acid residue in NSD1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12807965, 15942875, 24412544, 26690673). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Sep 02, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Sotos syndrome (MIM#117550). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated SET domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in at least ten individuals, some of which are reported de novo events, and is consistently classified as pathogenic by diagnostic laboratories in ClinVar (PMIDs:12464997, 27834868, 30719864). (SP) 1102 - Strong phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Likely pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Jan 01, 2016	This variant was classified as: Likely pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn	-	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Dec 11, 2020

Identified in multiple patients with Sotos Syndrome (Douglas et al., 2003; Tatton-Brown et al., 2005; Saugier-Veber et al., 2007; Kotilainen et al., 2009; Ha et al., 2016); Published functional studies demonstrate a damaging effect on the histone methyltransferase (HMT) activity (Qiao et al., 2011); 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: 16010675, 17565729, 12464997, 21196496, 15942875, 19876911, 27834868, 30719864) -

Hypertelorism;C0036439:Scoliosis;C0344482:Hypoplasia of the corpus callosum;C0454644:Delayed speech and language development;C0557874:Global developmental delay;C1837658:Delayed gross motor development;C3276036:High anterior hairline Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

May 14, 2014

- -

Osteopenia;C0032914:Preeclampsia;C0043094:Increased body weight;C0239676:High forehead;C0241240:Tall stature;C0454644:Delayed speech and language development;C1844505:Pointed chin;C1849265:Overgrowth;C2243051:Macrocephaly Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Dec 13, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.66	.;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	0.53	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.5	.;H;.
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-3.6	D;D;D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0060	D;D;D
Sift4G	Uncertain	0.0030	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.97
MutPred		0.97		.;Gain of ubiquitination at K2012 (P = 0.0716);.;
MVP		0.98
MPC		2.8
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.94
gMVP		0.99

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: rs587784177; hg19: chr5-176710828; COSMIC: COSV61777421; COSMIC: COSV61777421;