5-177283791-G-A

Position:

• chr5-177283791-G-A

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_022455.5(NSD1):​c.6014G>A​(p.Arg2005Gln) 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. Variant has been reported in ClinVar as Likely 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:5
• 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 15 ACMG points.

• PM1: In a strand (size 8) in uniprot entity NSD1_HUMAN there are 4 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 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, 0.938
• PP5: Variant 5-177283791-G-A is Pathogenic according to our data. Variant chr5-177283791-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 159395.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-177283791-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.6014G>A	p.Arg2005Gln	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.6014G>A	p.Arg2005Gln	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:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Sotos syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The missense c.6014G>A p.Arg2005Gln variant in NSD1 gene has been reported in heterozygous state in individuals affected with Sotos syndrome Douglas J et al. 2003. Functional study found R2005Q reduced the activity of the H3K36 HKMT Qiao et al., 2011. The p.Arg2005Gln variant is novel not in any individuals in gnomAD Exomes and 1000 Genomes. This variant has been reported to the ClinVar database as Likely Pathogenic/ Pathogenic. The amino acid change p.Arg2005Gln in NSD1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Arg at position 2005 is changed to a Gln changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -

Beckwith-Wiedemann syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 17, 2018

This sequence change replaces arginine with glutamine at codon 2005 of the NSD1 protein (p.Arg2005Gln). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be de novo in an individual affected with Sotos syndrome (PMID: 12464997), and in another individual referred for genetic testing of Sotos syndrome (PMID: 16247291). ClinVar contains an entry for this variant (Variation ID: 159395). Experimental studies have shown that this missense change has greatly reduced H3K36 histone methyltransferase activities in vitro (PMID: 21196496). The observation of one or more missense substitutions at this codon (p.Arg2005Gly) in affected individuals suggests that this may be a clinically significant residue (PMID: 26690673). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Oct 04, 2023

Segregates with disease in affected individuals from a single family referred for genetic testing at GeneDx; Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect through reduction of H3K36 histone lysine methyltransferase activity (Qiao et al., 2011); 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: 12464997, 33942996, 21196496, 27834868, 16247291, 16010675) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.68	.;D;.
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;.
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.94	D;D;D
MetaSVM	Uncertain	0.77	D
MutationAssessor	Benign	1.8	.;L;.
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-3.5	D;D;D
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0040	D;D;D
Sift4G	Uncertain	0.0060	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.71
MutPred		0.87		.;Gain of ubiquitination at K2003 (P = 0.0716);.;
MVP		0.96
MPC		2.8
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.89
gMVP		0.95

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: rs587784174; hg19: chr5-176710792; COSMIC: COSV100729769; COSMIC: COSV100729769;