rs797045825

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PP2PP3_StrongPP5_Very_Strong

The NM_022455.5(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 (★★).

Frequency

Genomes: not found (cov: 32)

Consequence

NSD1
NM_022455.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 9.32

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]

NSD1 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 17 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;

PP2

Missense variant in the NSD1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 137 curated pathogenic missense variants (we use a threshold of 10). The gene has 153 curated benign missense variants. Gene score misZ: 3.4113 (above the threshold of 3.09). Trascript score misZ: 5.7368 (above the threshold of 3.09). GenCC associations: The gene is linked to 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 rank	MANE	Protein	UniProt
NSD1	NM_022455.5 link	c.5990A>G	p.Tyr1997Cys	missense_variant	Exon 19 of 23	ENST00000439151.7	NP_071900.2	Q96L73-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NSD1	ENST00000439151.7 link	c.5990A>G	p.Tyr1997Cys	missense_variant	Exon 19 of 23	1	NM_022455.5	ENSP00000395929.2		Q96L73-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Sotos syndrome

Pathogenic:4

Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). -

Oct 17, 2014

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 27, 2021

MGZ Medical Genetics Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 26, 2024

Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Sep 20, 2016

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided

Pathogenic:1

Nov 15, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 211738). This variant is also known as 5989A/G, Y1996C. 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 not present in population databases (gnomAD no frequency). 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). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.53

BayesDel_noAF

Pathogenic

0.52

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.71

.;D;.

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

1.0

D;D;.

M_CAP

Pathogenic

0.72

MetaRNN

Pathogenic

0.99

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.7

.;H;.

PrimateAI

Pathogenic

0.93

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over