NM_022455.5:c.5623-22G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_022455.5(NSD1):c.5623-22G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0515 in 1,613,924 control chromosomes in the GnomAD database, including 2,509 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.049 ( 200 hom., cov: 32)

Exomes 𝑓: 0.052 ( 2309 hom. )

Consequence

NSD1
NM_022455.5 intron

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -2.49

Publications

7 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: ClinGen, Orphanet, G2P
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=-0.94).

BP6

Variant 5-177280543-G-A is Benign according to our data. Variant chr5-177280543-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 261592.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0748 is higher than 0.05.

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	UniProt
NSD1	NM_022455.5	MANE Select	c.5623-22G>A	intron	N/A	NP_071900.2
NSD1	NM_001409301.1		c.5623-22G>A	intron	N/A	NP_001396230.1	Q96L73-1
NSD1	NM_001409302.1		c.5623-22G>A	intron	N/A	NP_001396231.1	Q96L73-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
NSD1	ENST00000439151.7	TSL:1 MANE Select	c.5623-22G>A	intron	N/A	ENSP00000395929.2	Q96L73-1
NSD1	ENST00000347982.9	TSL:1	c.4750-22G>A	intron	N/A	ENSP00000343209.5	A0A8I5QJP2
NSD1	ENST00000936190.1		c.5623-22G>A	intron	N/A	ENSP00000606249.1

Frequencies

GnomAD3 genomes

AF:

0.0487

AC:

7408

AN:

152196

Hom.:

199

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0549

Gnomad AMI

AF:

0.0406

Gnomad AMR

AF:

0.0325

Gnomad ASJ

AF:

0.0153

Gnomad EAS

AF:

0.0177

Gnomad SAS

AF:

0.0815

Gnomad FIN

AF:

0.0419

Gnomad MID

AF:

0.0475

Gnomad NFE

AF:

0.0516

Gnomad OTH

AF:

0.0435

GnomAD2 exomes

AF:

0.0467

AC:

11660

AN:

249900

AF XY:

0.0485

show subpopulations

Gnomad AFR exome

AF:

0.0593

Gnomad AMR exome

AF:

0.0199

Gnomad ASJ exome

AF:

0.0186

Gnomad EAS exome

AF:

0.0190

Gnomad FIN exome

AF:

0.0435

Gnomad NFE exome

AF:

0.0500

Gnomad OTH exome

AF:

0.0469

GnomAD4 exome

AF:

0.0518

AC:

75708

AN:

1461610

Hom.:

2309

Cov.:

AF XY:

0.0528

AC XY:

38364

AN XY:

727132

show subpopulations

African (AFR)

AF:

0.0569

AC:

1905

AN:

33468

American (AMR)

AF:

0.0218

AC:

976

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0194

AC:

506

AN:

26134

East Asian (EAS)

AF:

0.0173

AC:

688

AN:

39700

South Asian (SAS)

AF:

0.0836

AC:

7214

AN:

86248

European-Finnish (FIN)

AF:

0.0446

AC:

2383

AN:

53420

Middle Eastern (MID)

AF:

0.0671

AC:

387

AN:

5768

European-Non Finnish (NFE)

AF:

0.0527

AC:

58536

AN:

1111758

Other (OTH)

AF:

0.0515

AC:

3113

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

3619

7237

10856

14474

18093

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2204

4408

6612

8816

11020

<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:

0.0487

AC:

7417

AN:

152314

Hom.:

200

Cov.:

AF XY:

0.0478

AC XY:

3560

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.0549

AC:

2280

AN:

41554

American (AMR)

AF:

0.0325

AC:

497

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.0153

AC:

AN:

3470

East Asian (EAS)

AF:

0.0177

AC:

AN:

5186

South Asian (SAS)

AF:

0.0814

AC:

393

AN:

4828

European-Finnish (FIN)

AF:

0.0419

AC:

445

AN:

10610

Middle Eastern (MID)

AF:

0.0544

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0515

AC:

3507

AN:

68036

Other (OTH)

AF:

0.0458

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

370

740

1109

1479

1849

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

168

252

336

420

<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:

0.0500

Hom.:

Bravo

AF:

0.0469

Asia WGS

AF:

0.0930

AC:

324

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (1)

Sotos syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.94

CADD

Benign

0.0020

(source)

DANN

Benign

0.62

PhyloP100

-2.5

Mutation Taster

=100/0

polymorphism (auto)

(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.

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

Computational scores

Splicing

Publications

Other links and lift over