5-177212121-G-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_022455.5(NSD1):c.3722G>C(p.Ser1241Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000752 in 1,614,004 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00067 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00076 ( 0 hom. )

Consequence

NSD1
NM_022455.5 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.519

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 -19 ACMG points.

PP2

Missense variant where missense usually causes diseases, NSD1

BP4

Computational evidence support a benign effect (MetaRNN=0.003676474).

BP6

Variant 5-177212121-G-C is Benign according to our data. Variant chr5-177212121-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 159313.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-177212121-G-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00067 (102/152134) while in subpopulation AMR AF= 0.00308 (47/15254). AF 95% confidence interval is 0.00238. There are 0 homozygotes in gnomad4. There are 55 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High AC in GnomAd at 102 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NSD1	NM_022455.5 linkuse as main transcript	c.3722G>C	p.Ser1241Thr	missense_variant	5/23	ENST00000439151.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NSD1	ENST00000439151.7 linkuse as main transcript	c.3722G>C	p.Ser1241Thr	missense_variant	5/23	1	NM_022455.5	P2	Q96L73-1

Frequencies

GnomAD3 genomes

AF:

0.000671

AC:

102

AN:

152016

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000266

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00309

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000647

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000688

AC:

173

AN:

251414

Hom.:

AF XY:

0.000522

AC XY:

AN XY:

135892

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00249

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000703

Gnomad OTH exome

AF:

0.000814

GnomAD4 exome

AF:

0.000761

AC:

1112

AN:

1461870

Hom.:

Cov.:

AF XY:

0.000696

AC XY:

506

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.000119

Gnomad4 AMR exome

AF:

0.00233

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000868

Gnomad4 OTH exome

AF:

0.000629

GnomAD4 genome

AF:

0.000670

AC:

102

AN:

152134

Hom.:

Cov.:

AF XY:

0.000739

AC XY:

AN XY:

74376

show subpopulations

Gnomad4 AFR

AF:

0.000265

Gnomad4 AMR

AF:

0.00308

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000647

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000325

Hom.:

Bravo

AF:

0.000861

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.000502

AC:

EpiCase

AF:

0.000654

EpiControl

AF:

0.000711

ClinVar

Significance: Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Sotos syndrome

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Oct 27, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 08, 2013

- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 26, 2017

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Weaver syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.37

Cadd

Benign

Dann

Benign

0.96

Eigen

Benign

-0.91

Eigen_PC

Benign

-0.93

FATHMM_MKL

Benign

0.10

LIST_S2

Benign

0.75

T;T;.

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.0037

T;T;T

MetaSVM

Benign

-0.45

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.40

N;N;N

REVEL

Benign

0.049

Sift

Uncertain

0.0060

D;D;D

Sift4G

Benign

0.50

T;T;T

Polyphen

0.034

B;B;B

Vest4

0.17

MVP

0.57

MPC

0.053

ClinPred

0.012

GERP RS

0.13

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.045

gMVP

0.20

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