5-177248165-ATT-AT

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_022455.5(NSD1):c.4498-10delT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0227 in 1,613,718 control chromosomes in the GnomAD database, including 534 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.017 ( 31 hom., cov: 32)

Exomes 𝑓: 0.023 ( 503 hom. )

Consequence

NSD1
NM_022455.5 intron

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 1.52

Publications

1 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 -16 ACMG points.

BP6

Variant 5-177248165-AT-A is Benign according to our data. Variant chr5-177248165-AT-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 96059.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0168 (2550/152224) while in subpopulation NFE AF = 0.0273 (1855/68020). AF 95% confidence interval is 0.0262. There are 31 homozygotes in GnomAd4. There are 1212 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 2550 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	UniProt
NSD1	NM_022455.5	MANE Select	c.4498-10delT	intron	N/A	NP_071900.2
NSD1	NM_001409301.1		c.4498-10delT	intron	N/A	NP_001396230.1	Q96L73-1
NSD1	NM_001409302.1		c.4498-10delT	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.4498-15delT	intron	N/A	ENSP00000395929.2	Q96L73-1
NSD1	ENST00000347982.9	TSL:1	c.3625-15delT	intron	N/A	ENSP00000343209.5	A0A8I5QJP2
NSD1	ENST00000936190.1		c.4498-15delT	intron	N/A	ENSP00000606249.1

Frequencies

GnomAD3 genomes

AF:

0.0168

AC:

2553

AN:

152106

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00391

Gnomad AMI

AF:

0.0296

Gnomad AMR

AF:

0.00779

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00849

Gnomad FIN

AF:

0.0300

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0273

Gnomad OTH

AF:

0.00961

GnomAD2 exomes

AF:

0.0169

AC:

4237

AN:

250542

AF XY:

0.0170

show subpopulations

Gnomad AFR exome

AF:

0.00463

Gnomad AMR exome

AF:

0.00630

Gnomad ASJ exome

AF:

0.00199

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0307

Gnomad NFE exome

AF:

0.0250

Gnomad OTH exome

AF:

0.0168

GnomAD4 exome

AF:

0.0233

AC:

34034

AN:

1461494

Hom.:

503

Cov.:

AF XY:

0.0230

AC XY:

16696

AN XY:

727004

show subpopulations

African (AFR)

AF:

0.00329

AC:

110

AN:

33472

American (AMR)

AF:

0.00677

AC:

302

AN:

44636

Ashkenazi Jewish (ASJ)

AF:

0.00153

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.0114

AC:

982

AN:

86186

European-Finnish (FIN)

AF:

0.0307

AC:

1640

AN:

53338

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0268

AC:

29789

AN:

1111878

Other (OTH)

AF:

0.0178

AC:

1073

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

1812

3625

5437

7250

9062

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1066

2132

3198

4264

5330

<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:

0.0168

AC:

2550

AN:

152224

Hom.:

Cov.:

AF XY:

0.0163

AC XY:

1212

AN XY:

74422

show subpopulations

African (AFR)

AF:

0.00390

AC:

162

AN:

41530

American (AMR)

AF:

0.00778

AC:

119

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3470

East Asian (EAS)

AF:

0.000386

AC:

AN:

5178

South Asian (SAS)

AF:

0.00829

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0300

AC:

318

AN:

10600

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0273

AC:

1855

AN:

68020

Other (OTH)

AF:

0.00951

AC:

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

123

246

368

491

614

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

160

<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:

0.0138

Hom.:

Bravo

AF:

0.0140

Asia WGS

AF:

0.00491

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (3)

not provided (2)

Sotos syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.5

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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