Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_022455.5(NSD1):c.3796+22A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00139 in 857,108 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00074 ( 0 hom., cov: 26)

Exomes 𝑓: 0.0015 ( 1 hom. )

Consequence

NSD1
NM_022455.5 intron

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.167

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BP6

Variant 5-177212217-A-T is Benign according to our data. Variant chr5-177212217-A-T is described in ClinVar as Likely_benign. ClinVar VariationId is 261585.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000745 (71/95354) while in subpopulation AMR AF = 0.00138 (13/9394). AF 95% confidence interval is 0.000818. There are 0 homozygotes in GnomAd4. There are 37 alleles in the male GnomAd4 subpopulation. Median coverage is 26. This position passed quality control check.

BS2

High AC in GnomAd4 at 71 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022455.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
NSD1	NM_022455.5	MANE Select	c.3796+22A>T	intron	N/A	NP_071900.2
NSD1	NM_001409301.1		c.3796+22A>T	intron	N/A	NP_001396230.1
NSD1	NM_001409302.1		c.3796+22A>T	intron	N/A	NP_001396231.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
NSD1	ENST00000439151.7	TSL:1 MANE Select	c.3796+22A>T	intron	N/A	ENSP00000395929.2
NSD1	ENST00000347982.9	TSL:1	c.2923+22A>T	intron	N/A	ENSP00000343209.5
NSD1	ENST00000687453.1		c.3487+22A>T	intron	N/A	ENSP00000508426.1

Frequencies

GnomAD3 genomes

AF:

0.000745

AC:

AN:

95330

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000500

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00138

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:

0.000948

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00256

AC:

161

AN:

62938

AF XY:

0.00230

show subpopulations

Gnomad AFR exome

AF:

0.000845

Gnomad AMR exome

AF:

0.00270

Gnomad ASJ exome

AF:

0.000303

Gnomad EAS exome

AF:

0.000899

Gnomad FIN exome

AF:

0.00125

Gnomad NFE exome

AF:

0.00353

Gnomad OTH exome

AF:

0.00283

GnomAD4 exome

AF:

0.00147

AC:

1122

AN:

761754

Hom.:

Cov.:

AF XY:

0.00140

AC XY:

537

AN XY:

383948

show subpopulations

African (AFR)

AF:

0.000214

AC:

AN:

18724

American (AMR)

AF:

0.00101

AC:

AN:

26750

Ashkenazi Jewish (ASJ)

AF:

0.000215

AC:

AN:

13986

East Asian (EAS)

AF:

0.0000330

AC:

AN:

30318

South Asian (SAS)

AF:

0.000206

AC:

AN:

53366

European-Finnish (FIN)

AF:

0.000295

AC:

AN:

30554

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3694

European-Non Finnish (NFE)

AF:

0.00187

AC:

1031

AN:

551856

Other (OTH)

AF:

0.00111

AC:

AN:

32506

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.410

Heterozygous variant carriers

127

169

211

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

132

176

220

<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

AF:

0.000745

AC:

AN:

95354

Hom.:

Cov.:

AF XY:

0.000812

AC XY:

AN XY:

45554

show subpopulations

African (AFR)

AF:

0.000499

AC:

AN:

22032

American (AMR)

AF:

0.00138

AC:

AN:

9394

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2416

East Asian (EAS)

AF:

0.00

AC:

AN:

1208

South Asian (SAS)

AF:

0.00

AC:

AN:

2594

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5816

Middle Eastern (MID)

AF:

0.00

AC:

AN:

196

European-Non Finnish (NFE)

AF:

0.000948

AC:

AN:

49566

Other (OTH)

AF:

0.00

AC:

AN:

1336

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000572

Hom.:

Bravo

AF:

0.000593

ClinVar

ClinVar submissions as Germline

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

2.0

(source)

DANN

Benign

0.45

PhyloP100

-0.17

Mutation Taster

=100/0

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

rs111663030

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over