rs797045825

Positions:

• chr5-177282562-A-G
• chr5-177282562-A-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.5990A>G​(p.Tyr1997Cys) 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. Y1997H) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NSD1 ENST00000439151.7 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 9.32

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 chr5-177282561-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 159392.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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, 0.993
• PP5: Variant 5-177282562-A-G is Pathogenic according to our data. Variant chr5-177282562-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 211738.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-177282562-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NSD1	NM_022455.5	c.5990A>G	p.Tyr1997Cys	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.5990A>G	p.Tyr1997Cys	missense_variant	19/23	1	NM_022455.5	ENSP00000395929	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Sotos syndrome Pathogenic:5

Likely pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Dec 27, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	-	In-silico prediction tools (REVEL, CADD) are consistent in predicting that the variant to be disease-causing and affect protein function. Monoallelic variants in ABCA1 gene are associated with HDL deficiency, familial 1 (MIM#604091). -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 13, 2022	This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 1997 of the NSD1 protein (p.Tyr1997Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of NSD1-related conditions (PMID: 12807965). In at least one individual the variant was observed to be de novo. This variant is also known as 5989A/G, Y1996C. ClinVar contains an entry for this variant (Variation ID: 211738). 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. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Oct 17, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center	Jun 26, 2024	This sequence variant is a single nucleotide substitution (A>G) at position 5990 of the coding sequence of the NSD1 gene that results in a tyrosine to cysteine amino acid change at residue 1997 of the Nuclear Receptor-Binding SET Domain-Containing Protein 1. Variants in the NSD1 gene have been previously shown to be associated with Sotos syndrome, often de novo, but can be inherited (PMID: 12464997, 12525543). This is a previously reported variant (ClinVar 211738) and has been reported in individuals affected by an NSD1-related disorder (PMID: 21084978, 15942875). This variant is absent in the gnomAD v4.1.0 population database (0 in approximately 1,610,000 alleles). Multiple bioinformatic tools predict that this amino acid change would be damaging, and the Tyr1997 residue at this position is highly conserved across the vertebrate species examined. In vitro functional studies showed the p.Tyr1997Cys mutation results in reduced or abolished enzyme methylation activity (PMID:24412544). Haploinsufficiency in NSD1 is a known mechanism of disease (PMID:11896389 ). Based upon the evidence, we consider this variant to be pathogenic. ACMG Criteria: PM2, PP3, PS2, PS3 -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 20, 2016

The p.Y1997C pathogenic mutation (also known as c.5990A>G), located in coding exon 18 of the NSD1 gene, results from an A to G substitution at nucleotide position 5990. The tyrosine at codon 1997 is replaced by cysteine, an amino acid with highly dissimilar properties. This mutation was first reported to be de novo in a patient with childhood overgrowth, dysmorphic facial features, and advanced bone age (Rio M et al. J. Med. Genet., 2003 Jun;40:436-40). It has subsequently been reported in multiple individuals with Sotos syndrome phenotypes (Tatton-Brown K et al. Am. J. Hum. Genet., 2005 Aug;77:193-204; Choufani S et al. Nat Commun, 2015 Dec;6:10207). Additionally, in vitro functional studies showed the p.Y1997C mutation results in reduced or abolished enzyme methylation activity (Kudithipudi S et al. Chem. Biol., 2014 Feb;21:226-37). Based on the supporting evidence, p.Y1997C is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.71	.;D;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	1.0	D;D;.
M_CAP	Pathogenic	0.72	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.7	.;H;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-8.0	D;D;D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.95
MutPred		0.97		.;Loss of sheet (P = 0.0315);.;
MVP		0.98
MPC		2.9
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.92
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: rs797045825; hg19: chr5-176709563; COSMIC: COSV100729066; COSMIC: COSV100729066;