rs374110615

Variant names:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 1P and 10B. PP2BP4BP6BS1BS2

The NM_022455.5(NSD1):c.8048A>G(p.Gln2683Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000167 in 1,614,104 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

NSD1
NM_022455.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: 5.36

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 -9 ACMG points.

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.

BP4

Computational evidence support a benign effect (MetaRNN=0.39498708).

BP6

Variant 5-177295416-A-G is Benign according to our data. Variant chr5-177295416-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 282745.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000118 (18/152224) while in subpopulation AFR AF= 0.000434 (18/41464). AF 95% confidence interval is 0.00028. There are 0 homozygotes in gnomad4. There are 10 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 18 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NSD1	NM_022455.5 link	c.8048A>G	p.Gln2683Arg	missense_variant	Exon 23 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.8048A>G	p.Gln2683Arg	missense_variant	Exon 23 of 23	1	NM_022455.5	ENSP00000395929.2		Q96L73-1

Frequencies

GnomAD3 genomes

AF:

0.000118

AC:

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000434

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

251304

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135892

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000616

AC:

AN:

1461880

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.000269

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.000118

AC:

AN:

152224

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74368

show subpopulations

Gnomad4 AFR

AF:

0.000434

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000986

Hom.:

Bravo

AF:

0.000128

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Oct 13, 2016

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sotos syndrome

Uncertain:1

Jul 15, 2021

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases

Benign:1

Dec 20, 2023

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.082

BayesDel_noAF

Uncertain

0.0

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.11

.;T;.

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.81

T;T;.

M_CAP

Uncertain

0.22

MetaRNN

Benign

0.39

T;T;T

MetaSVM

Uncertain

0.71

MutationAssessor

Benign

0.55

.;N;.

PrimateAI

Benign

0.43

PROVEAN

Benign

-0.88

N;N;N

REVEL

Uncertain

0.40

Sift

Pathogenic

0.0

D;D;D

Sift4G

Uncertain

0.014

D;D;D

Polyphen

0.99

D;D;D

Vest4

0.22

MVP

0.81

MPC

0.64

ClinPred

0.40

GERP RS

5.0

Varity_R

0.59

gMVP

0.28

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