rs530920626

Positions:

chr5-177257068-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 3P and 16B. PM1PP2BP4_StrongBP6_Very_StrongBS2

The ENST00000439151.7(NSD1):c.4883T>C(p.Met1628Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000551 in 1,614,150 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000060 ( 4 hom. )

Consequence

NSD1
ENST00000439151.7 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 1.37

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

PM1

In a zinc_finger_region PHD-type 2 (size 56) in uniprot entity NSD1_HUMAN there are 23 pathogenic changes around while only 4 benign (85%) in ENST00000439151.7

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.

BP4

Computational evidence support a benign effect (MetaRNN=0.012027651).

BP6

Variant 5-177257068-T-C is Benign according to our data. Variant chr5-177257068-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 159349.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAdExome4 at 87 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NSD1	NM_022455.5 linkuse as main transcript	c.4883T>C	p.Met1628Thr	missense_variant	13/23	ENST00000439151.7	NP_071900.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NSD1	ENST00000439151.7 linkuse as main transcript	c.4883T>C	p.Met1628Thr	missense_variant	13/23	1	NM_022455.5	ENSP00000395929	P2	Q96L73-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000219

AC:

AN:

251474

Hom.:

AF XY:

0.000177

AC XY:

AN XY:

135912

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00121

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00163

GnomAD4 exome

AF:

0.0000595

AC:

AN:

1461880

Hom.:

Cov.:

AF XY:

0.0000509

AC XY:

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00121

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000267

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.0000993

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152270

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000422

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.000321

AC:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Sotos syndrome

Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Sep 02, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 28, 2020	- -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	NSD1: BP4, BS1 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 08, 2020	This variant is associated with the following publications: (PMID: 14571271) -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 08, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.23

CADD

Benign

DANN

Benign

0.70

DEOGEN2

Benign

0.086

.;T;.

Eigen

Benign

-0.81

Eigen_PC

Benign

-0.68

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.21

T;T;.

M_CAP

Benign

0.043

MetaRNN

Benign

0.012

T;T;T

MetaSVM

Benign

-0.51

MutationAssessor

Benign

0.30

.;N;.

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-0.83

N;N;N

REVEL

Benign

0.25

Sift

Benign

0.66

T;T;T

Sift4G

Benign

0.60

T;T;T

Polyphen

0.0

B;B;B

Vest4

0.37

MutPred

0.46

.;Gain of phosphorylation at M1628 (P = 0.1459);.;

MVP

0.26

MPC

0.82

ClinPred

0.0041

GERP RS

0.71

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.023

gMVP

0.71

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