Genetic Variant NSD1:c.4966+43G>C (chr5-177257194-G-C) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_022455.5(NSD1):c.4966+43G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000076 in 1,184,288 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000067 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000077 ( 0 hom. )

Consequence

NSD1
NM_022455.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.33

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 -8 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BS2

High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NSD1	NM_022455.5 link	c.4966+43G>C		intron_variant	Intron 13 of 22	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.4966+43G>C		intron_variant	Intron 13 of 22	1	NM_022455.5	ENSP00000395929.2		Q96L73-1

Frequencies

GnomAD3 genomes

AF:

0.00000674

AC:

AN:

148336

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000149

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000443

AC:

AN:

225676

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000991

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000772

AC:

AN:

1035952

Hom.:

Cov.:

AF XY:

0.00000945

AC XY:

AN XY:

528930

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26080

American (AMR)

AF:

0.00

AC:

AN:

41334

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22982

East Asian (EAS)

AF:

0.00

AC:

AN:

36192

South Asian (SAS)

AF:

0.00

AC:

AN:

74674

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4896

European-Non Finnish (NFE)

AF:

0.0000109

AC:

AN:

733160

Other (OTH)

AF:

0.00

AC:

AN:

46008

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.588

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000674

AC:

AN:

148336

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

72192

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

40452

American (AMR)

AF:

0.00

AC:

AN:

14894

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3418

East Asian (EAS)

AF:

0.00

AC:

AN:

5024

South Asian (SAS)

AF:

0.00

AC:

AN:

4672

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9666

Middle Eastern (MID)

AF:

0.00

AC:

AN:

308

European-Non Finnish (NFE)

AF:

0.0000149

AC:

AN:

66964

Other (OTH)

AF:

0.00

AC:

AN:

2040

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

0.85

(source)

DANN

Benign

0.76

PhyloP100

-1.3

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

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chr5-177257194-G-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over