chr5-177204280-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6BP7BS2

The NM_022455.5(NSD1):c.1224A>G(p.Gly408Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000123 in 1,461,540 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: not found (cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

NSD1
NM_022455.5 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.589

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

Beckwith-Wiedemann syndrome due to NSD1 mutation
Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
Sotos syndrome
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P, ClinGen
Sotos syndrome 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics

NSD1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.49).

BP6

Variant 5-177204280-A-G is Benign according to our data. Variant chr5-177204280-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 159261. Variant chr5-177204280-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 159261. Variant chr5-177204280-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 159261. Variant chr5-177204280-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 159261. Variant chr5-177204280-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 159261. Variant chr5-177204280-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 159261. Variant chr5-177204280-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 159261. Variant chr5-177204280-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 159261. Variant chr5-177204280-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 159261. Variant chr5-177204280-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 159261. Variant chr5-177204280-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 159261. Variant chr5-177204280-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 159261. Variant chr5-177204280-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 159261. Variant chr5-177204280-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 159261. Variant chr5-177204280-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 159261. Variant chr5-177204280-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 159261. Variant chr5-177204280-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 159261. Variant chr5-177204280-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 159261. Variant chr5-177204280-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 159261. Variant chr5-177204280-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 159261. Variant chr5-177204280-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 159261. Variant chr5-177204280-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 159261. Variant chr5-177204280-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 159261.

BP7

Synonymous conserved (PhyloP=0.589 with no splicing effect.

BS2

High AC in GnomAdExome4 at 18 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NSD1	NM_022455.5 link	c.1224A>G	p.Gly408Gly	synonymous_variant	Exon 4 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.1224A>G	p.Gly408Gly	synonymous_variant	Exon 4 of 23	1	NM_022455.5	ENSP00000395929.2		Q96L73-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000278

AC:

AN:

251402

AF XY:

0.0000515

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000123

AC:

AN:

1461540

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

727088

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.0000447

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86212

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53374

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000126

AC:

AN:

1111792

Other (OTH)

AF:

0.0000166

AC:

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.000102

Hom.:

Bravo

AF:

0.0000113

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Sotos syndrome

Uncertain:2

Jul 08, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Apr 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

NSD1-related disorder

Benign:1

Sep 20, 2022

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.49

CADD

Benign

(source)

DANN

Benign

0.73

PhyloP100

0.59

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over